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

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.

Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment

“…De novo drug discovery remains challenging due to the lack of validated targets and the cost of clinical development (14). To address this problem, we utilized an in silico drug repositioning approach to identify existing FDA-approved drugs for applications based on gene expression profiles (15).…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…Validation increases confidence in a target or pathway prior to significant investments in the development of a molecule. Put simply, the usefulness of any chemical tools that emerge from a discovery program depends on the biologic relevance of the target (Hoelder et al, 2012). Validation of a putative target can be achieved via a range of strategies, such as genetic knockdown or knockout (RNAi, CRISPR/Cas) or overexpression of targets (gain-of-function), using both cell lines and mouse models (including xenografts) (Benson et al, 2006).…”

Addressing the Right Targets in Oncology: Challenges and Alternative Approaches

“…To be a good drug target, the original observation must ideally be robust enough to bear examination in multiple related systems using multiple well-validated reagents and a variety of orthogonal techniques that lead to supportive conclusions. 66 A key lesson from the workflow described above is the need to account for the well-recognized off-target effects of RNAi. 61 Probes against the target should be employed from multiple independent suppliers with a full provision of positive (e.g., death-inducing RNAi probes such as PLK1) and negative control probes in all experiments.…”