Observation Open Access
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Clin Oncol. Jan 10, 2012; 3(1): 1-6
Published online Jan 10, 2012. doi: 10.5306/wjco.v3.i1.1
Serendipity in anticancer drug discovery
Emily Hargrave-Thomas, Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
Bo Yu, Jóhannes Reynisson, School of Chemical Sciences, The University of Auckland, Auckland 1142, New Zealand
Author contributions: Hargrave-Thomas E collected and analysed the data and wrote the manuscript; Yu B analysed the data; and Reynisson J provided scientific supervision.
Correspondence to: Dr. Jóhannes Reynisson, School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.reynisson@auckland.ac.nz
Telephone: +64-9-3737599 Fax: +64-9-3737422
Received: September 22, 2011
Revised: December 19, 2011
Accepted: January 7, 2012
Published online: January 10, 2012

Abstract

It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered following an incident in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind.

Key Words: Anticancer drugs; Drug discovery and development; Serendipity



INTRODUCTION

It is well know that serendipity has played a pivotal role in the discovery of many drugs used today[1-3]. Indeed two major classes of anticancer drugs were discovered with the aid of serendipity, i.e., Barnett Rosenberg’s discovery of cisplatin and the breakthrough observation by Lieutenant Colonel Stewart F Alexander that the chemical warfare agent, nitrogen mustard, depleted white blood cell numbers; aiding in the development of alkylation agents[1-2]. The question therefore emerges of how important serendipity really is in drug discovery and development? The aim of this investigation is to identify all marketed drugs and their derivatives used in the clinic today in which discovery was in some way based on or aided by a serendipitous event. The numbers obtained will be compared to the total number of marketed drugs resulting in a quantitative measure of the impact of serendipity in the discovery of pharmaceuticals, and anticancer drugs in particular.

METHODOLOGY

Three books were analysed: Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use[1], Happy Accidents: Serendipity in Modern Medical Breakthroughs[2] and Drug Discovery, a History[3]. Furthermore, one scientific paper was identified with a list of drugs discovered by the aid of serendipity[4]. The books and the paper are shown in Table 1. These resources were studied and the stories containing serendipitous events were recorded. The nature of the serendipitous findings were categorised as laboratory based or clinical. The drugs identified were reviewed in DrugBank[5-7] and only those that were approved, were small molecules, and in clinical use were included. Furthermore, drugs with similar chemical structures and with the same notation (i.e., used to treat the same condition) as the parent drug were considered to be their derivatives as identified by substructure and Tanimoto similarity searching in DrugBank[5-7]. A full list of the drugs found is given in Tables 2 and 3.

Table 1 The sources used to identify serendipitous discoveries in drug development.
TitlesAuthors
Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We UseLi[1]
Happy Accidents: Serendipity in Modern Medical BreakthroughsMeyers[2]
Drug Discovery, a HistorySneader[3]
Chance favors the prepared mind-from serendipity to rational drug designKubinyi[4]
Table 2 List of drugs discovered by serendipitous events in the laboratory and their derivatives.
Serendipitous drugsDerivativesNo. of derivatives
AcetanilideAcetaminophen1
AcetohexamideTolbutamide, glimepiride, glibenclamide, glipizide, chlorpropamide, gliquidone, tolazamide, gliclazide8
CaptoprilRamipril, fosinopril, lisinopril, trandolapril, enalapril, perindopril, spirapril, quinapril8
CisplatinOxaliplatin, carboplatin2
DiethylstilbestrolDienestrol1
DigoxinDigitoxin, deslanoside, acetyldigitoxin, ouabain4
ErgotamineDihydroergotamine, dihydroergotoxine, ergoloidmesylate, methysergide, methylergonovine, ergonovine6
EphedrinePseudoephedrine, ritodrine, metaraminol, phenylephrine, isoetharine, fenoterol, epinephrine, orciprenaline, terbutaline9
GriseofulvinNA0
HeparinPentosan, polysulfate, enoxaparin, ardeparin, fondaparinux sodium4
lsoniazidNA0
LidocainePrilocaine, tocainide, mepivacaine, bupivacaine, levobupivacaine, ropivacaine6
LithiumNA0
MarinolNabilone1
MechlorethamineChlorambucil, cyclophosphamide, melphalan, uracil mustard, estramustine5
MecillinamPivmecillinam1
MethotrexateLeucovorin1
Nalidixic acidRosoxacin, enoxacin, pefloxacin, norfloxacin, lomefloxacin, ciprofloxacin, levofloxacin, ofloxacin8
NitroglycerineErythrityl tetranitrate, Isosorbide dinitrate2
PenicillinAmpicillin, amoxicillin, azidocillin, azlocillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, flucloxacillin, hetacillin, meticillin, mezlocillin, nafcillin, oxacillin, penicillin g, penicillin V, piperacillin, pivampicillin, tazobactam, ticarcillin21
PentamidineNA0
PhysostigmineNA0
QuinineQuinidine1
SorafenibNA0
StreptomycinFramycetin, neomycin, josamycin, tobramycin, kanamycin, candicidin, spectinomycin7
SulfanilamideSilver sulfadiazine, sulfacetamide, sulfacytine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamerazine, sulfamethizole, sulfametopyrazine, sulfamethoxazole, sulfamoxole, sulfapyridine, sulfisoxazole13
Valproic acidDivalproex sodium1
VinblastineVincristine, vindesine, vinorelbine3
DicoumarolNA0
WarfarinAcenocoumarol, phenprocoumon, dicumarol3
Zinc SulfateNA0
Table 3 List of drugs discovered to be beneficial for conditions other than for which they were developed (clinical).
Off-label drugs DerivativesNo. of derivatives
AminoglutethimideNA0
AlprostadilDinoprostone, carboprost, tromethamine, dinoprost, tromethamine, misoprostol4
AmphetaminePhentermine, methamphetamine, dextroamphetamine, alverine, selegiline, mephentermine, tranylcypromine, phenelzine, benzphetamine, diethylpropion10
AspirinNA0
AuranofinNA0
CarbamazepineOxcarbazepine1
CelecoxibNA0
ChlordiazepoxideDiazepam, temazepam, oxazepam, fludiazepam, clorazepate, halazepam, prazepam, flurazepam, lorazepam, cinolazepam, clonazepam, nitrazepam, bromazepam, flunitrazepam, quazepam, clotiazepam, alprazolam, estazolam, adinazolam, midazolam20
ChlorothiazideBenzthiazide, diazoxide, hydrochlorothiazide, hydroflumethiazide, bendroflumethiazide, cyclothiazide, polythiazide, trichlormethiazide, methyclothiazide, furosemide, bumetanide11
ClofibrateFenofibrate1
DactinomycinNA0
DiisopropylfluorophosphateNA0
DiltiazemNA0
DimenhydrinateNA0
DiphenhydramineBromodiphenhydramine, diphenylpyraline2
DiphenoxylateLoperamide1
DipyridamoleNA0
DisulfiramNA0
DoxorubicinEpirubicin, daunorubicin, idarubicin, valrubicin, plicamycin5
EtomidateNA0
FinasterideDutasteride1
GuanethidineDebrisoquin, guanidine2
HaloperidolDroperidol1
ImatinibNA0
ImipramineTrimipramine, desipramine, clomipramine, protriptyline, amitriptyline, nortriptyline, cyclobenzaprine, maprotiline, doxepin, amoxapine10
IproniazidIsocarboxazid1
LinezolidNA0
Lysergic acid diethylamideCabergoline, lisuride, bromocriptine, nicergoline, pergolide5
MeprobamateCarisoprodol1
MercaptopurineThioguanine, azathioprine2
MetronidazoleTinidazole1
MifepristoneNA0
MinoxidilNA0
Mycophenolic acidMycophenolatemofetil1
NaloxoneNaltrexone1
NorethindroneLevonorgestrel, norgestrel, etonogestrel, gestodene,desogestrel, medroxyprogesterone, megestrol, progesterone, drospirenone, norelgestromin, ethynodioldiacetate11
PethidineAnileridine1
PhenobarbitalMethylphenobarbital, secobarbital, metharbital, aprobarbital, primidone, methsuximide6
PrednisoneMedrysone, methylprednisolone, prednisolone, rimexolone, fluocortolone, desoximetasone6
ProbenecidNA0
ProcarbazineNA0
PromethazineAcepromazine, aceprometazine, acetophenazine, arphenazine, chlorpromazine, ethopropazine, fluphenazine, mesoridazine, methotrimeprazine, perphenazine, pipotiazine, prochlorperazine, promazine, propericiazine, propiomazine, thioproperazine, thioridazine, trifluoperazine, triflupromazine, trimeprazine20
QuinacrineChloroquine, primaquine, hydroxychloroquine, amodiaquine4
ReserpineDeserpidine, rescinnamine2
Salicyclic acidSalsalate, olsalazine, diflunisal, mesalazine4
SildenafilTadalafil, vardenafil2
SirolimusEverolimus1
TamoxifenToremifene1
TerfenadineFexofenadine1
ThalidomideLenalidomide1
TolazolineNA0
TrimethadioneParamethadione1
ZidovudineTrifluridine, telbivudine, idoxuridine, zalcitabine, stavudine5
SERENDIPITY IN DRUG DISCOVERY

Serendipity refers to chance discoveries that have been exploited with sagacity[3]. This requires both a chance event and the mental ability to understand the occurrence and realise its potential. In this work, only stories that fit both requirements for serendipity were recorded. The serendipitous events were divided into two categories; laboratory based and clinical. A classic example of the former is Barnett Rosenberg’s discovery of cisplatin, and for the latter dimenhydrinate (Dramamine), which was developed as an antihistamine but is now sold as a travel sickness medication due to a chance observation/realisation by one of the participants in the clinical trials. The division of the drugs into these two categories is not always obvious, but we believe that it helps in the analysis of the results. In his book, Serendipity, Roberts[8] coined the term pseudoserendipity to describe accidental discoveries of ways to achieve an end sought for in contrast to the meaning of true serendipity, which describes accidental discoveries of things not sought for. Certainly all of the drugs discovered in the clinic can be described as pseudoserendipitous according to this definition and many of the drugs found in the laboratory.

To calculate the proportion of drugs with a serendipitous background, the total number of small molecule drugs on the market (FDA approved) is taken to be 1437 according to DrugBank[5-7]. Overington et al[9] reported 1204 small molecule drugs in clinical use, which is a somewhat smaller number.

In this analysis, 84 drugs were identified to have serendipitous events aiding their discovery, which is 5.8% of all drugs currently in use. Thirty-one drugs (2.2%) were identified in the laboratory and 116 derivatives (8.1%) of these drugs were identified as shown in Table 4. Fifty-three pharmaceuticals (3.7%) were discovered in clinical settings and 147 derivatives (10.2%) of these were identified (Table 4). Therefore, in total there are 347 drugs currently on the market, in which discovery was aided by a serendipitous event, representing a staggering 24.1% of all drugs currently on the market. A graphical representation of these results is shown in Figure 1.

Figure 1
Figure 1 The distribution of the serendipity types (laboratory-based and clinical) and their chemical derivatives in clinical use (100% = 1437).
Table 4 List of drugs discovered with the aid of serendipity in the laboratory, the number of identified derivatives and their therapeutic notation.
DrugsRef.DerivativesNotation
Acetanilide[3,4]1Antipyretic
Acetohexamide[1,3,4]8Diabetes II
Captopril[1,3]8Cardiovascular
Cisplatin[1-4]2Cancer
Diethylstilbestrol[3,4]1Hormonal
Digoxin[1,3]4Cardiovascular
Ergotamine[1-3]6Cardiovascular
Ephedrine[3]9CNS
Griseofulvin[3,4]0Antifungal
Heparin[2-4]4Cardiovascular
Isoniazid[3,4]0Antibiotic
Lidocaine[3]6CNS
Lithium[1-4]0CNS
Marinol[3]1CNS
Mechlorethamine[1-4]5Cancer
Mecillinam[3]1Antibiotic
Methotrexate[1,3]1Cancer
Nalidixic acid[1,3]8Antibiotic
Nitroglycerine[1,3,4]2Cardiovascular
Penicillin[1-4]21Antibiotic
Pentamidine[3]0Antiprotozoal
Physostigmine[3]0Ocular
Quinine[3]1Antiprotozoal
Sorafenib[1]0Cancer
Streptomycin[1,2]7Antibiotic
Sulfanilamide[1-3]13Antibiotic
Valproic acid[3,4]1CNS
Vinblastine[1-3]3Cancer
Dicoumarol[2-4]0Cardiovascular
Warfarin[2-4]3Cardiovascular
Zinc sulfate[3]0Wilson’s disease
SERENDIPITY IN ANTICANCER DRUG DISCOVERY AND DEVELOPMENT

According to DrugBank[5-7] there are 88 anticancer drugs in clinical use today. Of the drugs identified with serendipitous origin, 13 are used to treat cancer and 18 are their chemical derivatives. This means that 35.2% of all anticancer drugs in clinical use involved serendipity of some kind. The statistical distribution is shown in Figure 2. This represents a larger portion of serendipitous effects than for pharmaceuticals in general.

Figure 2
Figure 2 The statistical distribution of anticancer drugs discovered with the aid of serendipity and their chemical derivatives in clinical use (100% = 88).

Of the primary serendipitous events, anticancer drugs represent 15.5% (13/84), i.e., a sizeable portion. However, relatively few derivatives were found for anticancer drugs (6.8% of the derivatives). This highlights the difficulty in developing effective anticancer drugs.

When the primary serendipitous events are investigated, it is clear that antibiotic, anticancer, cardiovascular and central nervous system (CNS) drugs are the most common notations with about 10 events for each (Tables 5). Other therapeutic fields such as antiprotozoal and antifungal are also reported. Less common treatments for conditions such as gout and alcoholism are reported. A high frequency of CNS discoveries is seen in the clinical settings in Table 5, i.e., 17 out of a total of 53. This reflects the difficulty in developing drugs that need to pass the Blood-Brain-Barrier (e.g., reference[10] and references therein), and the dearth of biochemical assays modelling the diseases of the mind and pain.

Table 5 List of drugs found to be beneficial for conditions other than for which they were developed (clinical), the number of identified derivatives and their therapeutic notation.
Clinical drugsRef.DerivativesNotation
Aminoglutethimide[3,4]0Cancer
Alprostadil[3]4Cardiovascular
Amphetamine[1,3,4]10CNS
Aspirin[1-3]0Cardiovascular/Cancer
Auranofin[2,3]0Antirheumatic
Carbamazepine[3]1CNS
Celecoxib[2]0Cancer
Chlordiazepoxide[1-4]20CNS
Chlorothiazide[1,3,4]11Diuretic
Clofibrate[3]1Cardiovascular
Dactinomycin[3]0Cancer
Diisopropylfluorophosphate[3]0Ocular
Diltiazem[3]0Cardiovascular
Dimenhydrinate[2-4]0CNS
Diphenhydramine[3]2CNS
Diphenoxylate[3,4]1Antidiarrheal
Dipyridamole[3]0Cardiovascular
Disulfiram[1,2,4]0Alcoholism treatment
Doxorubicin[3]5Cancer
Etomidate[3,4]0CNS
Finasteride[2]1Baldness
Guanethidine[3,4]2Cardiovascular
Haloperidol[1,3,4]1CNS
Imatinib[1]0Cancer
Imipramine[1-4]10CNS
Iproniazid[1-4]1CNS
Linezolid[1]0Antibiotic
LSD[1-4]5CNS
Meprobamate[2,4]1CNS
Mercaptopurine[1,3]2Immunosuppressive
Metronidazole[3]1Antiprotozoal
Mifepristone[3,4]0Hormonal
Minoxidil[2]0Cardiovascular
Mycophenolic acid[3]1Immunosuppressive
Naloxone[3]1CNS
Norethindrone[1,3,4]11Hormonal
Pethidine[3,4]1CNS
Phenobarbital[3]6CNS
Prednisone[3,4]6Anti-inflammatory
Probenecid[2]0Gout
Procarbazine[3]0CNS
Promethazine[1-3]20Antihistamine
Quinacrine[3]4Antiprotozoal
Reserpine[1-3]2CNS
Salicyclic acid[3]4Antirheumatic
Sildenafil[1-3]2Erectile dysfunction
Sirolimus[3]1Immunosuppressive
Tamoxifen[1-4]1Cancer
Terfenadine[3]1Antihistamine
Thalidomide[1,2]1Cancer
Tolazoline[3]0Cardiovascular
Trimethadione[3]1CNS
Zidovudine[1,2]5Antiviral
KNOWN DRUG SPACE

Recently a new concept of Known Drug Space (KDS) has been developed to help drug designers to navigate chemical space based on the analysis of drugs in clinical use[11-13]. It is known that 10% of KDS are unaltered natural products and 29% are their derivatives (semi-synthetics)[14]. With this fact and the results presented in this paper it can be stated that KDS is, to a large extent, populated by chance rather than design. Therefore, the analysis of the physicochemical properties of known drugs gives a region of property space that really works for successful pharmaceuticals.

DISCUSSION

Serendipity in drug discovery has not been investigated to a great extent, however, some papers were found in the literature and the opinions expressed vary greatly, which is not surprising due to the ambiguous nature of this phenomenon. For instance, Jeste et al[15] downplay the importance of serendipity arguing that few if any discoveries in their field of psychiatry were truly serendipitous. Conversely, Lombardino and Lowe state that “the role of serendipity, chemical intuition and creativity in thoughtfully selecting a chemical target to synthesize in order to discover the best-quality drug has not diminished” irrespective of the introduction of new technologies[16]. Furthermore, Klein strongly believes that a loss of chance observations and unexpected clinical benefits are due to recent changes in the process of drug discovery[17]. He criticises cost-control measures which remove a creative environment in hospitals that fosters serendipity[17]. Finally, Kubinyi[4] suggests that researchers should not be manipulated by short-term business cycles; drug discoveries require good science, enlightened management, and freedom for researchers to act, challenge dogma and take risks.

This investigation provides a limited scope of serendipitous drug discovery since only four sources were analysed. It is certain that not all serendipitous events are recorded; researchers may choose not to report them in favour of standard scientific methods of inquiry. It can therefore be argued that the impact of serendipity is even larger than found in this investigation.

According to the results presented here, approximately 24% of all drugs currently on the market were discovered with the aid of serendipity and thus, may never have been discovered without the curiosity, observation, and sagacity of the researchers. This serves to highlight the unpredictability in drug research and the necessity to allow for and encourage freedom in research directions and promote the intellectual freedom of the scientists involved. Also, a sound education in science is indispensable and the promotion of critical thinking of our students is vital (for further discussion see Lenox[18]).

The term “drug repositioning” is sometimes used when a new notation is found for a drug molecule. A good example is the reintroduction of the infamous thalidomide in clinical use. This is obviously a very positive development since new drugs do not have to be developed from scratch with a large price tag. As shown in this work, serendipitous events in the clinic are important and have facilitated drug repositioning emphasising the need to educate clinicians about this phenomenon.

Understanding the serendipity phenomenon is crucial so we can start to manipulate it to our advantage and we believe that quantifying the impact of serendipity facilitates our understanding of it. Finally, Pasteur’s comment on serendipity certainly still holds true: “Dans les champs de l’observation, le hasard ne favoriseque les esprits prepares.” (“In the field of observation, chance favours only the prepared mind.”)

CONCLUSION

It was found that 35.2% of all the anticancer drugs now in clinical use were discovered by serendipity. In general, 24% of all pharmaceuticals currently on the market were affected in a positive way during their development by this phenomenon with CNS active drugs being the most prominent. This leads to the conclusion that drug discovery is based on good science and where intuition, critical thinking, sagacity and open-mindedness play crucial roles.

Footnotes

Peer reviewers: Arianna L Kim, PhD, Herbert Irving Assistant Professor of Dermatology, Department of Dermatology, Columbia Medical Center, 1130 St. Nicholas Ave 321B, New York, NY 10032, United States; Shufeng Zhou, MD, PhD, A/Professor, School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia

S- Editor Yang XC L- Editor Webster JR E- Editor Li JY

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