Small molecules, big impact: 20 years of targeted therapy in oncology

Summary

The identification of molecular targets and the growing knowledge of their cellular functions have led to the development of small molecule inhibitors as a major therapeutic class for cancer treatment. Both multitargeted and highly selective kinase inhibitors are used for the treatment of advanced treatment-resistant cancers, and many have also achieved regulatory approval for early clinical settings as adjuvant therapies or as first-line options for recurrent or metastatic disease. Lessons learned from the development of these agents can accelerate the development of next-generation inhibitors to optimise the therapeutic index, overcome drug resistance, and establish combination therapies. The future of small molecule inhibitors is promising as there is the potential to investigate novel difficult-to-drug targets, to apply predictive non-clinical models to select promising drug candidates for human evaluation, and to use dynamic clinical trial interventions with liquid biopsies to deliver precision medicine.

Introduction

Cancer chemotherapy uses drugs to kill cancer cells that are more primed for death than non-malignant host cells. The focus of novel drug development has shifted towards the identification and targeting of molecular drivers of cancer. There are two main approaches for targeted cancer therapy: antibodies and small molecules. Antibodies are typically characterised by high selectivity; however, their targets are often restricted to the cell surface and they require intravenous or subcutaneous dosing because of their large molecular weight. By comparison, small molecule inhibitors vary in selectivity, and by virtue of their small size, can potentially bind a wider range of extracellular and intracellular targets. To date, there are 43 small molecule inhibitors approved by the US Food and Drug Administration (FDA) for oncology indications (table). Although most of these approvals were based on the prolonged survival of patients with advanced cancer that were refractory to conventional chemotherapy, many of these drugs show superiority over cytotoxic chemotherapy, with fewer side-effects as first-line therapy in the recurrent or metastatic setting. There are also examples of small molecule inhibitors that are approved as treatment for minimal residual disease or as adjuvant therapy delivered with curative intent (appendix pp 1–4). Most approved small molecule inhibitors target intracellular kinases that regulate cell signalling through the transfer of phosphate groups to target proteins (figure 1). A broad range of targets are currently being investigated, including those involved in protein–protein interactions, cancer metabolism, and immune modulation. We review the development of multitargeted and biomarker-selected small molecule inhibitors, discuss unresolved issues, and predict future directions for this continuously evolving field.