Therapeutic antibodies that block the PD-1/PD-L1 interaction have rapidly become a key backbone of cancer therapy. A small molecule targeting the same interaction could have several advantages over an antibody, such as oral administration, higher penetration into the tumor, lack of systemic immunogenicity, and ease of manufacture. Here we disclose for the first time our PD-L1 inhibitor GS-4224 which is currently undergoing clinical trials. Utilizing protein X-ray crystallography, we discovered a lead series which was then optimized for cellular potency and the desired DMPK profile. Detailed mechanism of action studies revealed that the small molecule induced PD-L1 dimerization translated from in-vitro (biochemical, primary cells, whole blood) to the in-vivo setting and provided a convenient measure of target engagement. GS-4224 was studied in a MC38 mouse tumor model where it demonstrated equivalent efficacy to a clinically approved antibody. In SAD and MAD phase I clinical studies GS-4224 was well tolerated and showed promising target engagement.

GS-4224: A potent, oral small molecule PD-L1 inhibitor

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ACS Fall 2022

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