Chemical biology approaches to target validation in cancer

•Target validation is especially critical in the context of drugging the cancer genome and clinical drug resistance.•We review how chemical biology approaches benefit target validation.•We illustrate how critically assessed small molecule chemical inhibitors complement genetic approaches.•We highlight recent progress, including reagents for less druggable targets.

Target validation is a crucial element of drug discovery. Especially given the wealth of potential targets emerging from cancer genome sequencing and functional genetic screens, and also considering the time and cost of downstream drug discovery efforts, it is essential to build confidence in a proposed target, ideally using different technical approaches. We argue that complementary biological and chemical biology strategies are essential for robust target validation. We discuss recent progress in the discovery and application of high quality chemical tools and other chemical biology approaches to target validation in cancer. Among other topical examples, we highlight the emergence of designed irreversible chemical tools to study potential target proteins and oncogenic pathways that were hitherto regarded as poorly druggable.