| Autor: |
Ma C; Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China., Kang D; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Gao P; Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China., Zhang W; Hits Discovery, Jacobio Pharmaceuticals, Beijing 101111, China., Wu X; Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China., Xu Z; Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China., Han H; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Zhang L; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Cai Y; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Wang Y; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Wang Y; Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China., Long W; Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China. |
| Abstrakt: |
As an oncogenic phosphatase, SHP2 acts as a converging node in the RTK-RAS-MAPK signaling pathway in cancer cells and suppresses antitumor immunity by passing signals downstream of PD-1. Here, we utilized the extra druggable pocket outside the previously identified SHP2 allosteric tunnel site by the (6,5 fused), 6 spirocyclic system. The optimized compound, JAB-3312 , exhibited a SHP2 binding K d of 0.37 nM, SHP2 enzymatic IC 50 of 1.9 nM, KYSE-520 antiproliferative IC 50 of 7.4 nM and p-ERK inhibitory IC 50 of 0.23 nM. For JAB-3312 , an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. JAB-3312 was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of JAB-3312 and the p-ERK inhibition in tumors. Currently, JAB-3312 is undergoing clinical trials as a potential anticancer agent. |
