Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Apr;6(2):155-76.
doi: 10.1016/j.molonc.2012.02.004. Epub 2012 Mar 3.

Discovery of small molecule cancer drugs: successes, challenges and opportunities

Swen Hoelder  1 , Paul A Clarke, Paul Workman
Affiliations
Review

Discovery of small molecule cancer drugs: successes, challenges and opportunities

Swen Hoelder et al. Mol Oncol. 2012 Apr.

Abstract

The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the 'Valley of Death' between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Examples of approved molecularly targeted cancer drugs.
Figure 2
Figure 2
Drug discovery and development: From gene to drug. The four key steps of cancer drug discovery that are covered in this review are highlighted in the centre. ‘Reverse translation’ from the clinic back to the laboratory is covered under the target validation and selection section. Modified with permission from (Collins and Workman, 2006).
Figure 3
Figure 3
An example of a representative screening cascade used for the discovery of small molecule HSP90 molecular chaperone inhibitors (Brough et al., 2007). The work flow begins with a fluorescence polarization (FP) assay and selectivity counter screens are used to identify active molecules that bind the desired target but not related proteins that need to be avoided. Active compounds progress down the screen sequence through in vitro cancer cell proliferation assays (here involving the sulforhodamine or SRB method) and molecular biomarker assays to confirm on‐target activity in the test cells. Compounds with suitable activity and ADME characteristics will progress further to in vivo pharmacokinetic and pharmacodynamic biomarker analysis in a mouse model. Upon overcoming these hurdles, promising compounds progress finally to in vivo efficacy studies in a relevant tumour model. These test cascade assays are run on compounds generated in successive iterative make‐and‐test cycles, so that the desired properties are progressively achieved. Note that the assays in the red boxes were used most frequently as the core test cascade. Other assays were run as required.
Figure 4
Figure 4
Choice of screening strategies for finding hit matter acting on the desired target. Most drug discovery project teams tend to use hit identification approaches that represent a mixture of design and screening elements. Increasing knowledge of the target facilitates the screening of fewer compounds, whereas if many compounds are screened little knowledge on the target is required.
Figure 5
Figure 5
Allosteric inhibitors of the kinase AKT/PKB.
Figure 6
Figure 6
Fragment‐based design of the BRAF inhibitor vemurafenib. Left‐hand side: A small fragment (4) was found by screening and optimised by fragment growing and knowledge of protein‐ligand crystal structures to eventually yield vemurafenib. The core structure found in both fragment hit and drug is depicted in red. Right‐hand side: Crystal structure of vemurafenib bound to BRAF (PDB code: 30G7).
Figure 7
Figure 7
Fragment linking approach leading to the discovery of the BLC‐2 family inhibitor ABT‐732, Left‐hand side: fragment linking. Right‐hand side: Crystal structure of 8 or ABT‐737 in complex with BCL‐XL (PDB code: 2YXJ).
Figure 8
Figure 8
Design of ABL inhibitors active against the T315I gatekeeper mutant that is resistant to imatinib, dasatinib and nilotinib. In the first step, it was shown that potent inhibition of ABL can be achieved by addressing a region of the ATP pocket that is not altered by the T315I mutant. The red part of 10 explores a region occupied in a similar manner by imatinib (9) through the moiety outlined in red. Further potency is gained through adding another substituent (outlined in blue) to 9 that interacts with Arg386 and Glu282. The clinical candidate DCC‐2036 (11) was then obtained by extending the compound further towards the 315 residue in a manner that is not obstructed by the T315I mutation (Chan et al., 2011).
Figure 9
Figure 9
An illustration of multidimensional optimisation leading to GDC‐0941, a pan‐Class I PI3K inhibitor that is currently in Phase II clinical trials (Folkes et al., 2008; Raynaud et al., 2009). The lead compound PI‐103 already showed promising biochemical and cellular activity (and is used as a chemical tool) but also exhibited poor physicochemical and pharmacokinetic properties. These were optimised through several rounds of synthesis and testing. Selectivity for PI3K versus DNA‐PK was also improved. The properties which initially did not fulfil our criteria are marked in red.
Figure 10
Figure 10
ERBB2 inhibitors with long residence times at the target. Lapatinib binds to an unusual conformation of the kinase and the half‐life of the complex is in the range of 5 h. Neratinib and afatinib engage in a convalent bond with Cys797 of EFGR through a reactive group (outlined in red). Right‐hand side: Crystal structure of neratinib bound to EGFR (PDB code: 2JIV).
Figure 11
Figure 11
Updated Pharmacologic Audit Trial. Reprinted with permission from (Yap et al., 2010).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abad-Zapatero, C. , Metz, J.T. , 2005. Ligand efficiency indices as guideposts for drug discovery. Drug Discov. Today. 10, 464–469. - PubMed
    1. Akella, L.B. , DeCaprio, D. , 2010. Cheminformatics approaches to analyze diversity in compound screening libraries. Curr. Opin. Chem. Biol.. 14, 325–330. - PubMed
    1. Allegra, C.J. , Jessup, J.M. , Somerfield, M.R. , Hamilton, S.R. , Hammond, E.H. , Hayes, D.F. , McAllister, P.K. , Morton, R.F. , Schilsky, R.L. , 2009. American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol.. 27, 2091–2096. - PubMed
    1. Ashworth, A. , Lord, Christopher J. , Reis-Filho, Jorge S. , 2011. Genetic interactions in cancer progression and treatment. Cell. 145, 30–38. - PubMed
    1. Baell, J.B. , Holloway, G.E. , 2010. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem.. 53, 2719–2740. - PubMed

MeSH terms

Substances