A Complete Pipeline for the Discovery and Development of Haptenizing Chimeras at Scale

Abstract

Covalent inhibitors are increasingly popular therapeutics. However, these drugs suffer from acquired resistance. A new therapeutic approach to treating cancer builds upon existing covalent inhibitors to repurpose them as Haptenizing Chimeras (HaCs), immunotherapeutic agents, to not just combat acquired resistance but function as a novel treatment modality to combat cancers of all types. The strength of HaCs lies in their versatility and scalability. We report a complete pipeline that leverages computational tools, cell-based assays, and solid-phase peptide synthesis to vastly scale the scope and efficiency of the discovery and development of HaCs. This pipeline greatly expanded the therapeutic reach of HaCs, having identified tens of thousands of new and promising targets. Utilization of the pipeline has also contributed to a near 3-times increase in efficacy of the molecules through linker exploration and discovery. It also allows us to respond to patient needs in real time. Finally, the pipeline takes a step towards turning the intracellular space into extracellular markers, potentially revolutionizing the ability to develop targeted therapeutics for different cancers.