Development of immune checkpoint inhibitors using DOTS - an innovative fragment-based drug design approach – ImmunoH2L

Though mainly discussed in the context of tumor control, immunotherapy has emerged as an effective strategy to combat pathogen infection by blocking immune checkpoint signaling. Likewise, the continued success of immunotherapies relies on the identification of novel targets, more effective treatment combinations, and reducing their toxicities. Small molecules offer unique advantages to solve these challenges due to their more flexible administration, greater tissue penetration, and the potential to create lower cost, broadly accessible medicines.
Recently, our team discovered and validated the first small molecule inhibitors of the SIRP?-CD47 immune checkpoint using an innovative fragment-based approach. The overall goal of the ImmunoH2L program is to develop our promising fragment hits into potent biologically active lead molecules using 2 complementary approaches established by our team : non-covalent fragment growing (DOTS) and covalent-based fragment growing (CovaDOTS). The successful development of potent small molecule-based inhibitors of SIRP?-CD47 will enable their translation as potential best-in-class immunotherapies as well as validate our unique drug development strategy for application to subsequent emerging immune checkpoints.