Therapeutic options for aggressive cancer types such as breast and lung remain limited; disease relapse and death occur in 30-60% of non-small cell lung cancer (NSCLC) patients, whereas in triple-negative breast cancer or TNBC, recurrence-free survival occurs in less than 30% patients. The kinases, MNK and p70S6K have been proposed as targets for the potential treatment of breast cancer (BC) and lung cancer but currently, no drug that was purposely designed to inhibit these kinases have been approved by the FDA for the treatment of BC or NSCLC. In this study, we have identified HSND80 (a morpholino nicotinamide analog of ponatinib) as a potent MNK/p70S6K inhibitor that has excellent activity against TNBC and NSCLC cell lines. HSND80 has a longer target residence time (τ) of 45 mins and 58 mins against MNK1 and MNK2 respectively, compared to τ of eFT508 (tomivosertib) against MNK1 and MNK2 (τ = 1 min and 5 min, respectively). Molecular dynamics simulation was used to provide some insights into the binding of HSND80 to MNK and p70S6K kinases. Western blotting analysis and phosphoproteomics analysis of the TNBC cell line, MDA-MB-231, revealed that phosphorylations of elF4E (MNK target) and elF4B and S6 (p70S6K targets) were reduced upon compound treatment, which is in line with the proposed mechanism of action; dual MNK/p70S6K targeting. HSND80 could be dosed orally at 15 and 30 mg/kg and at such doses, could reduce tumor volume in a syngeneic NSCLC mouse model.

Drug design strategies represent a fundamental challenge in chemical biology that could benefit from the development of next-generation high-throughput assays. Here we demonstrate that structural dynamic changes induced by ligand binding can be transmitted to a sensor protein fused to a target protein terminus. Here, NanoLuc luciferase, used as the intact protein or its α-complementation peptide, was fused to seven proteins from distinct enzyme superfamilies resulting in sensitive ligand-dependent bioluminescent outputs. This finding allows a general non-competitive, function-independent, quantitative, isothermal gain-of-signal ligand binding readout. As applied to chemical library high throughput screening, we can observe multivariate pharmacologic outputs including cofactor-induced synergy in ligand binding, as well as an example of allosteric site binding. The structural dynamics response assay format described here can enable the investigation of proteins precluded from study due to cost-prohibitive, insensitive, or technically challenging assays, including from cell lysates containing endogenously expressed gene edited proteins.

Data from in vitro and animal studies suggest that asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), synergizes with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) to prevent emergence of and overcome resistance. Combination therapy may provide new treatment options for patients with chronic myeloid leukemia (CML) with suboptimal responses to ATP-competitive TKI monotherapy. Preliminary analysis of asciminib combined with nilotinib, imatinib, or dasatinib in a phase 1 dose-escalation study suggested promising efficacy and safety for patients with CML in chronic phase or accelerated phase treated with prior ATP-competitive TKIs; herein, we present final results from the 3 combination therapy arms. Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy. Based on these safety, tolerability, and preliminary efficacy results, asciminib 40 mg twice daily (BID) plus nilotinib 300 mg BID, asciminib 40 or 60 mg once daily (QD) plus imatinib 400 mg QD, and asciminib 80 mg QD plus dasatinib 100 mg QD were identified as recommended doses for expansion. The maximum tolerated dose was reached at asciminib 60 mg QD plus imatinib 400 mg QD and was not reached with asciminib plus nilotinib or dasatinib.

Asciminib is the first approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). The present final analysis of the phase 1, open-label, nonrandomized trial (NCT02081378) assessed the long-term safety, tolerability, and antileukemic activity of asciminib in 115 patients with chronic myeloid leukemia in chronic phase without the BCR::ABL1T315I mutation who received asciminib 10-200 mg twice daily (BID) or 80-200 mg once daily (cutoff: March 14, 2023). Median exposure duration was 5.9 (range, 0-8.4) years; 60.9% of patients continued receiving asciminib through post-trial access. Grade ≥3 adverse events (AEs) occurred in 88 patients (76.5%). AEs led to treatment discontinuation, dose adjustment/interruption, or additional therapy in 15 (13.0%), 74 (64.3%), and 106 (92.2%) patients, respectively. Most first-ever AEs, particularly hematologic AEs, presented within the first year and no new safety signals emerged. Of 56 patients who achieved major molecular response, 50 maintained the response by cutoff; the Kaplan-Meier-estimated probability of maintaining this response for ≥432 weeks ( ≈ 8.3 years) was 88% (95% confidence interval, 78.2-97.0%). The recommended dose for expansion was determined at 40 mg BID. With up to 8.4 years of treatment, asciminib continued to demonstrate long-term safety and efficacy in this population.

Fluorine has become an essential element in the development of modern pharmaceuticals, due to its unique chemical properties that can significantly enhance the biological activity, metabolic stability, and lipophilicity of drug molecules. This review explores recent advancements in the synthesis and application of fluorine-containing drugs approved by the US Food and Drug Administration (FDA) in 2024. These novel drugs demonstrate improved efficacy and safety profiles, addressing a range of therapeutic areas including oncology, infectious diseases, metabolic disorders and genetic disorders that affect the adrenal glands. The incorporation of fluorine atoms into drug candidates has facilitated the development of molecules with optimized pharmacokinetic and pharmacodynamic properties, leading to better patient outcomes. The review further discusses the synthetic methodologies employed, the structural characteristics of these drugs, and their clinical implications, providing insights into the ongoing innovation within the pharmaceutical industry driven by fluorine chemistry.

The co-occurrence of JAK2 V617F mutations and the BCR::ABL1 translocation in the same patient is rare, and the current standard treatment for aggressive myeloid blast phase chronic myeloid leukemia (CML-myeloid BP) with JAK2 V617F mutations remains inadequate, particularly in transplant-ineligible patients. Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase that specifically targets the ABL1 myristoyl pocket, has emerged as a novel alternative to standard tyrosine kinase inhibitor (TKI) therapy. Ropeginterferon alfa-2b (ropegIFNα2b) is a novel site-selective, monopegylated recombinant human IFN with long-term safety and efficacy in patients with polycythemia vera (PV). Here, we report a case of successful combination therapy with asciminib and ropegIFNα2b in a patient with CML-myeloid BP who had a long history of PV with JAK2 V617F refractory to induction chemotherapy with several TKIs. The combination of asciminib and ropegIFNα2b is a promising new treatment option for these patients.

A facile approach for chemoselective synthesis of 2,3,5-trisubstituted pyridines and 2,5-disubstituted oxazoles from L-phenylalanine and aryl methyl ketone using I2/DMSO has been developed. Two equivalents of L-phenylalanine reacted with aryl methyl ketone and I2/DMSO giving 2,3,5-trisubstituted pyridines and interestingly one equivalent of L-phenylalanine afforded 2,5-disubstituted oxazoles. This chemo-divergent approach has features of being transition metal-free, free from expensive ligands, additives and starting materials, and having a less toxic nitrogen source and broad substrate scope.

There are many highly validated cancer targets that are difficult or impossible to drug due to the absence of suitable pockets that can bind small molecules. Fragment-based methods have been shown to be a useful approach for identifying ligands to proteins that were previously thought to be undruggable. In this review, I will give an overview of fragment-based ligand discovery and provide examples from our own work on how fragment-based methods were used to discover high affinity ligands for challenging cancer drug targets.

First-in-class drug discovery (FICDD) offers novel therapies, new biological targets and mechanisms of action (MOAs) toward targeting various diseases and provides opportunities to understand unexplored biology and to target unmet diseases. Current screening approaches followed in FICDD for discovery of hit and lead molecules can be broadly categorized and discussed under phenotypic drug discovery (PDD) and target-based drug discovery (TBDD). Each category has been further classified and described with suitable examples from the literature outlining the current trends in screening approaches applied in small molecule drug discovery (SMDD). Similarly, recent applications of functional genomics, structural biology, artificial intelligence (AI), machine learning (ML), and other such advanced approaches in FICDD have also been highlighted in the article. Further, some of the current medicinal chemistry strategies applied during discovery of hits and optimization studies such as hit-to-lead (HTL) and lead optimization (LO) have been simultaneously overviewed in this article.

More than half of the ~20,000 protein-encoding human genes have paralogs. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to subsets of paralogous proteins. Here we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs lacking the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we substituted the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-CCNE1-N112C interaction into in vitro NanoBRET (bioluminescence resonance energy transfer) and in cellulo activity-based protein profiling assays capable of identifying compounds that reversibly inhibit both the N112C mutant and wild-type CCNE1:CDK2 (cyclin-dependent kinase 2) complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings, thus, show how electrophile-cysteine interactions mapped by chemical proteomics can extend the understanding of protein ligandability beyond covalent chemistry.

The chronic myeloid leukemia is a malignant hematopoietic disorder in which the BCR-ABL kinase has been identified as the causative protein. The inhibitors targeting BCR-ABL kinase have been extensively employed in clinical management of chronic myeloid leukemia, significantly enhancing survival rates and prognosis for patients. Despite the extensive utilization of 1st to 4th generation BCR-ABL inhibitors in clinical therapy, the emergence of drug-resistant mutations necessitates an urgent quest for novel therapeutic strategies. The proteolysis targeting chimera technology represents an innovative strategy for protein degradation, directly degrading BCR-ABL fusion proteins while circumventing challenges associated with drug resistance. This review article provides an overview of current research progress on inhibitors and proteolysis targeting chimeras for the treatment of chronic myeloid leukemia through targeting BCR-ABL. We anticipate that this timely and comprehensive review will serve as a source of inspiration and guidance for pharmaceutical chemists in the development of highly potent BCR-ABL inhibitors and proteolysis targeting chimeras.

Fragment-Based Drug Discovery (FBDD) has revolutionized drug discovery by overcoming the challenges of traditional methods like combinatorial chemistry and high-throughput screening (HTS). Leveraging small, low-molecular-weight fragments, FBDD achieves higher hit rates, reduced screening costs, and faster development timelines for clinically relevant drug candidates. This review explores FBDD's core principles, innovative methodologies, and its success in targeting diverse protein classes, including previously "undruggable" targets. Key advancements in fragment libraries, screening techniques, and computational tools are discussed, along with the efficient progression from fragment hits to clinical drugs. Notably, we highlight FDA-approved fragment-derived drugs, including capivasertib, which has increased the total number of fragment-based oncology drugs to seven. As FBDD continues to evolve, its potential to address unmet therapeutic needs and drive the discovery of groundbreaking treatments across various disease areas becomes increasingly evident.

Chronic myeloid leukemia (CML) is a hematologic condition characterized by the overexpression of stem blood cells in the bone marrow. The Philadelphia chromosome encodes the oncogenic tyrosine kinase BCR-ABL, which is a hallmark of CML. Imatinib, a phenylamino pyrimidine derivative, was the first tyrosine kinase inhibitor (TKI) approved in 2001 for CML. Despite launching a new era in cancer targeted therapy, acquired resistance occurred due to the point mutation of a gatekeeper residue (Thr315Ile) at the BCR-ABL catalytic pocket. There are no approved medications for Thr315Ile-BCR-ABL harboring CML patients. Present study was aimed at the in silico identification of synthetically accessible imatinib derivatives that are likely to bind a frequent Thr315Ile-BCR-ABL and overcome drug resistance. 4-((4-benzylpiperazin-1-yl) methyl)-N-(4-methyl-3-(4-(pyridine-3-yl) pyrimidine-2-amino) phenyl) benzamide (SCHEMBL12127861) and 4-(methoxy (methyl) amino)-N-(3-methyl-5-(pyrido[3,4-b] pyrazin-2-yl thio) phenyl) benzamide (18) were revealed as top-binders. Molecular dynamics simulations and free energy calculations conferred stable binding features Thr315Ile-BCR-ABL. A new binding model was suggested for 18 that resided outside the kinase domain (∼15 Å from Ile315). Considering stability and binding energy compared to imatinib, the intended binding model may be the subject of further evaluations to overwhelm drug resistance. SCHEMBL12127861 had appropriate and more buried accommodation than imatinib near the DFG motif and P-loop of the kinase domain. Hydrogen bonds, π-cation interaction, salt bridge, and a vdW cooperative contacts mediated the complex stability. Although validation of proposed models is to be achieved, this study identified synthetically accessible in silico hits with tight binding to the clinically frequent mutant BCR-ABL phenotypes in Thr315Ile-positive CML patients.

In the evolving therapeutic landscape of chronic myeloid leukemia (CML), asciminib stands out as a critical treatment option. Its ability to bind to and allosterically modulate the myristoyl pocket of BCR::ABL1 enables asciminib to effectively overcome resistance to conventional tyrosine kinase inhibitors (TKIs). Asciminib has shown significant cytogenetic and molecular responses in heavily pretreated patients, those previously exposed to ponatinib, and treatment-naïve individuals, attributed to its pharmacological selectivity and generally favorable safety profile. Asciminib also offers a compelling alternative for patients with a history of cardiovascular events or unfavorable cardiovascular profiles. However, extended follow-up in ongoing trials is necessary for a thorough assessment of its long-term benefits. Mutations in the myristoyl pocket, such as A337V/T and I502L, along with kinase domain mutations, including F359C/I/V at the kinase-SH2 interface and M244V in the N-lobe, have demonstrated the ability to undermine asciminib effectiveness in clinical practice, highlighting the importance of mutational assessment before starting treatment. This review provides an in-depth analysis of the preclinical and clinical evidence supporting the use of asciminib, synthesizing findings from a targeted literature search of PubMed and Web of Science. Our discussion integrates insights into its mechanism of action, clinical efficacy, safety, resistance patterns, and future directions.

The original population pharmacokinetics (popPK) model for asciminib in patients with chronic myeloid leukemia in chronic phase (CML-CP) was refined to address drug development needs in support of drug submission, namely, attainment of target drug exposure in specific patient populations, populating individual daily exposures for exposure-response analyses of key efficacy and safety endpoints, confirmation of comparability in exposure between 40 mg b.i.d. and 80 mg q.d., and assessment of ethnic insensitivity.

Participants from two organ dysfunction studies, patients with CML in blast and acute phases and acute lymphoblastic leukemia and patients from a phase III efficacy study in newly diagnosed Ph + CML-CP, and data from a dedicated phase II study in the Chinese patients previously treated with at least two prior tyrosine kinase inhibitors, and a phase IIIb study comparing two dose regimens of asciminib (40 mg b.i.d. and 80 mg q.d.) were included in the revised popPK model. Covariates evaluated were line of therapy, baseline renal and hepatic functions, Chinese or Japanese ethnicity.

The apparent clearance and steady-state volume of distribution of asciminib were 6.84 L/h and 110 L, respectively, for a typical individual of 70 kg weight and 90 mL/min absolute glomerular filtration rate. Both the 40 mg b.i.d. and 80 mg q.d. resulted in a steady-state daily AUC of 12,600 ng.h/mL, and there was no difference between lines of therapy. Effects of renal or hepatic impairment on clearance were not clinically relevant. Chinese and Japanese exhibited similar PK as that of the global population.

The 40 mg b.i.d. and 80 mg q.d. regimens are comparable in their daily exposure, supporting the use of the two dosing regimens in newly diagnosed and previously treated CML-CP patients. The PK of asciminib is insensitive to ethnic differences and no dose adjustment is required for severe renal and hepatic impaired patients.

BCR-ABL1 kinase is a critical driver of chronic myeloid leukemia (CML) pathophysiology. The approval of allosteric inhibitor asciminib brings new hope for overcoming drug resistance caused by mutations in the ATP-binding site. To expand the chemical diversity of BCR-ABL1 kinase inhibitors with positive anti-tumor effect with asciminib, structure-based virtual screening and molecular dynamics simulations were employed to discover novel scaffolds. This approach led to the identification of a series of N-(2-acetamidobenzo[d]thiazol-6-yl)-2-phenoxyacetamide derivatives as new BCR-ABL1 inhibitors. The most potent compound, 10m, demonstrated inhibition of BCR-ABL-dependent signaling and showed an anti-tumor effect against K562 cells, with an IC50 value of 0.98 μM. Compound 10m displayed powerful synergistic anti-proliferation and pro-apoptotic effects when combined with asciminib, highlighting its potential as a promising lead for the development of potential BCR-ABL inhibitors.

Pyrazole and its derivatives have attracted considerable attention in pharmaceutical and medicinal chemistry, as reflected in their presence in numerous FDA-approved drugs and clinical candidates. This review presents a comprehensive analysis of articles published between 2014 and 2024, focusing on the microwave-, ultrasound-, and mechanochemical-assisted synthesis of pyrazole derivatives with anticancer activity. It explores synthetic methodologies, anticancer efficacy, and molecular docking studies, underscoring the significance of pyrazole derivatives in drug discovery and medicinal chemistry. Notably, microwave irradiation stands out as the most widely employed technique, providing high efficiency by significantly reducing reaction times while maintaining moderate temperatures. Ultrasound irradiation serves as a valuable alternative, particularly for processes that require milder conditions, whereas mechanochemical activation, though less frequently employed, offers distinct advantages in terms of sustainability.

Over the past two decades, tyrosine kinase inhibitors (TKIs) have rapidly emerged as pivotal targeted agents, offering promising therapeutic prospects for patients. However, as the cornerstone of targeted therapies, an increasing number of TKIs have been found to develop acquired resistance during treatment, making the challenge of overcoming this resistance a primary focus of current research. This review comprehensively examines the evolution of TKIs from multiple perspectives, with particular emphasis on the mechanisms underlying acquired resistance, innovative drug design strategies, inherent challenges, and future directions.

The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr-Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon-alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr-Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase-driven diseases. It provides valuable insights and strategies that may guide the development of next-generation therapies.

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.

Protein kinase inhibitors designed to compete with ATP as a primary mode of action turn out to have considerable effects that go beyond their interference of nucleotide binding. New research shows how kinase activation and sometimes noncatalytic functions of protein kinases can be controlled by allosteric properties of kinase inhibitors, communicating perturbations from the active site to distal regulatory regions.

Eukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered a promising anticancer target. Here we screen a fragment library against eIF4E and identify a ligand-binding site with previously unknown function. Follow-up structure-based design yields a low nM tool compound (4, Kd = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, and demonstrates target engagement with eIF4E in intact cells (EC50 = 2 µM). By coupling targeted protein degradation with genetic rescue using eIF4E mutants, we show that disruption of both the canonical eIF4G and non-canonical binding sites is likely required to drive a strong cellular effect. This work highlights the power of fragment-based drug discovery to identify pockets in difficult-to-drug proteins and how this approach can be combined with genetic characterization and degrader technology to probe protein function in complex biological systems.

Ponatinib and asciminib are approved for third-line therapy in chronic-phase chronic myeloid leukemia (CP-CML) and are the only drugs approved for patients with the T315I mutation in the United States. In Europe, only ponatinib is approved for patients with the T315I mutation.

Clinical trials evaluating ponatinib or asciminib in patients with relapsed and refractory (R/R) CP-CML who failed one or more second-generation TKIs or had the T315I mutation were identified in a systematic review of medical literature databases. A matching-adjusted indirect comparison (MAIC) analysis with individual patient-level data with ponatinib was used to balance baseline characteristics between ponatinib and asciminib groups. After matching, the response rate was calculated using the MAIC weight for each patient and the difference in response rate was calculated using a two-independent proportion Z-test. Cumulative rates of BCR::ABL1 IS ≤1% and major molecular response (MMR) in patients without baseline response were compared. Patients were further stratified by T315I mutation status.

The MAIC included four trials (ponatinib: NCT02467270, NCT01207440; asciminib: NCT02081378, NCT03106779). In patients without baseline response of BCR::ABL1 IS ≤1%, the adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 9.33% (95% confidence interval [CI]: 0.79%-17.86%; adjusted MMR rate difference: 6.84% [95% CI: -0.95%-14.62%]) by 12 months in favor of ponatinib. In patients with the T315I mutation, adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 43.54% (95% CI: 22.20%-64.87%; adjusted MMR rate difference: 47.37% [95% CI: 28.72%-66.02%]) by 12 months.

After key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15 h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Patients with chronic myeloid leukemia (CML) who have failed conventional tyrosine kinase inhibitors (cTKIs) and asciminib constitute a complex group of patients with few therapeutic options. A retrospective descriptive multicenter observational study was carried out including patients with CML who had presented a therapeutic failure to ≥ 2 cTKIs and asciminib, and had received or were not candidates to ponatinib. Of the 19 patients enrolled, 8 patients failed asciminib due to intolerance and 11 due to resistance. The most common strategy for intolerant patients was to initiate a previously administered cTKI (6/8) with dose adjustments or symptomatic management of adverse events (AEs). Of the patients who failed due to resistance, only patients who underwent progenitor transplantation achieved profound long-term responses. A frequent strategy was to use ponatinib (4/11) in patients previously considered non-candidates, with poor responses in patients in whom dose reductions were used, and severe AEs in patients at standard doses. In the remaining patients, cTKIs and other agents (interferon, hydroxyurea, citarabine, busulfan) were used with poor responses. Patients who progressed to advanced stages had a dismal prognosis. With a median follow-up of 11.2 months, overall survival of the global cohort was 73%; 100% for intolerant patients, 71% for resistant patients and 25% for those who discontinue asciminib in accelerated/blastic phase.

Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.

Up to 40% of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) discontinue treatment by 5 years, primarily due to resistance or intolerance. Rates of resistance to second-line (2L) treatment are also high. Some patients with resistance respond with dose escalation of tyrosine kinase inhibitors (TKIs). Asciminib demonstrated safety and efficacy across a broad dosage range. ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, dose-escalation study of asciminib in 2L and first-line treatment of CML-CP. The primary end point is major molecular response at 12 months in 2L. Secondary end points include molecular responses at and by scheduled time points, survival, and safety. ASC2ESCALATE is the first study investigating asciminib in CML-CP following failure of one prior TKI.Clinical Trial Registration: NCT05384587 (ClinicalTrials.gov).

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.

In the past several years there has been rapid adoption of artificial intelligence (AI) and machine learning (ML) tools for drug discovery. In this Microperspective, we comment on recent AI/ML applications to the discovery of allosteric modulators, focusing on breakthroughs with AlphaFold, structure-based drug discovery (SBDD), and medicinal chemistry applications. We discuss how these technologies are facilitating drug discovery and the remaining challenges to identify allosteric binding sites and ligands.

Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).

In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.

A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).

In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

The identification of chemical starting points for the development of molecular glues is challenging. Here, we employed fragment screening and identified an allosteric stabilizer of the complex between 14-3-3 and a TAZ-derived peptide. The fragment binds preferentially to the 14-3-3/TAZ peptide complex and shows moderate stabilization in differential scanning fluorimetry and microscale thermophoresis. The binding site of the fragment was predicted by molecular dynamics calculations to be distant from the 14-3-3/TAZ peptide interface, located between helices 8 and 9 of the 14-3-3 protein. This site was confirmed by nuclear magnetic resonance and X-ray protein crystallography, revealing the first example of an allosteric stabilizer for 14-3-3 protein-protein interactions.

Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.

Asciminib is a first-in-class BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket (STAMP). It is approved worldwide and in Japan for chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to previous tyrosine kinase inhibitor (TKI) therapy. In the Phase 3 ASCEMBL study, patients with CML-CP who received ≥ 2 prior ATP-competitive TKIs were randomized (2:1) to asciminib 40 mg twice-daily or bosutinib 500 mg once-daily. Here, we report the 96-week results of the subgroup analysis of Japanese patients (asciminib, n = 13; bosutinib, n = 3) in the ASCEMBL study. The MMR rate at Week 96 was 46.2% in asciminib-treated patients, increasing from Weeks 24 and 48. Patients who achieved MMR at Week 24 remained in MMR up to the Week 96 cutoff. While a high proportion of patients treated with asciminib remained on treatment at cutoff, none randomized to bosutinib were on treatment at Week 96. Despite the longer duration of exposure to asciminib, its safety and tolerability continued to be favorable with no new or worsening safety findings. Overall, the efficacy and safety outcomes in the Japanese subgroup were comparable with the ASCEMBL global study population, which supports the use of asciminib in Japanese patients with previously treated CML-CP.

Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development.

Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.

PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens.

Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.

Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from the active sites into which the allosteric ligand will dock and do not account for exactly how the active site is altered. Favorable allosteric inhibitors dock into sites that are nearby the active sites and follow nature, mimicking diverse allosteric regulation strategies.

The following article underscores the immense significance of allostery in drug design, describes current allosteric strategies, and especially offers a direction going forward. The article concludes with the authors' expert perspectives on the subject.

To select a productive venue in allosteric inhibitor development, we should learn from nature. Currently, useful strategies follow this route. Consider, for example, the mechanisms exploited in relieving autoinhibition and in harnessing allosteric degraders. Mimicking compensatory, or rescue mutations may also fall into such a thesis, as can molecular glues that capture features of scaffolding proteins. Capturing nature and creatively tailoring its mimicry can continue to innovate allosteric drug discovery.