8or1

Publication Abstract from PubMed

Novel 2-arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) benzylamine derivatives were designed, synthesized, and evaluated in vitro and in vivo against cancers as PD-1/PD-L1 inhibitors. Through the computer-aided structural optimization and the homogeneous time-resolved fluorescence (HTRF) assay, compound A56 was found to most strongly block the PD-1/PD-L1 interaction with an IC(50) value of 2.4 +/- 0.8 nM and showed the most potent activity. (1)H NMR titration results indicated that A56 can tightly bind to the PD-L1 protein with K(D) < 1 muM. The X-ray diffraction data for the cocrystal structure of the A56/PD-L1 complex (3.5 A) deciphered a novel binding mode in detail, which can account for its most potent inhibitory activity. Cell-based assays further demonstrated the strong ability of A56 as an hPD-1/hPD-L1 blocker. Especially in an hPD-L1 MC38 humanized mouse model, A56 significantly inhibited tumor growth without obvious toxicity, with a TGI rate of 55.20% (50 mg/kg, i.g.). In conclusion, A56 is a promising clinical candidate worthy of further development.

Design, Synthesis, and Antitumor Activity Evaluation of 2-Arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) Benzylamine Derivatives as Potent PD-1/PD-L1 Inhibitors.,Zhang H, Zhou S, Plewka J, Wu C, Zhu M, Yu Q, Musielak B, Wang X, Awadasseid A, Magiera-Mularz K, Wu Y, Zhang W J Med Chem. 2023 Jul 26. doi: 10.1021/acs.jmedchem.3c00731. PMID:37496104^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.