Fragment-Based Drug Discovery: Small Fragments, Big Impact - Success Stories of Approved Oncology Therapeutics

Fragment-Based Drug Discovery (FBDD) has revolutionized drug discovery by overcoming the challenges of traditional methods like combinatorial chemistry and high-throughput screening (HTS). Leveraging small, low-molecular-weight fragments, FBDD achieves higher hit rates, reduced screening costs, and faster development timelines for clinically relevant drug candidates. This review explores FBDD's core principles, innovative methodologies, and its success in targeting diverse protein classes, including previously "undruggable" targets. Key advancements in fragment libraries, screening techniques, and computational tools are discussed, along with the efficient progression from fragment hits to clinical drugs. Notably, we highlight FDA-approved fragment-derived drugs, including capivasertib, which has increased the total number of fragment-based oncology drugs to seven. As FBDD continues to evolve, its potential to address unmet therapeutic needs and drive the discovery of groundbreaking treatments across various disease areas becomes increasingly evident.