Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China.
Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China.
J Med Chem. 2024 Aug 22;67(16):13534-13549. doi: 10.1021/acs.jmedchem.4c00360. Epub 2024 Aug 7.
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, , exhibited a SHP2 binding of 0.37 nM, SHP2 enzymatic IC of 1.9 nM, KYSE-520 antiproliferative IC of 7.4 nM and p-ERK inhibitory IC of 0.23 nM. For , an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of and the p-ERK inhibition in tumors. Currently, is undergoing clinical trials as a potential anticancer agent.
作为致癌磷酸酶，SHP2 作为癌 细 胞中 RTK-RAS-MAPK 信号通路的汇聚节点，通过 PD-1 下游信号传递来抑制抗肿瘤免疫。在此，我们利用先前通过（6,5 稠合），6 螺环系统在已确定的 SHP2 变构隧道位点之外鉴定的额外可成药口袋。优化后的化合物 ，表现出 SHP2 结合的 IC50 为 0.37 nM，SHP2 酶的 IC50 为 1.9 nM，对 KYSE-520 的抗增殖 IC50 为 7.4 nM，对 p-ERK 的抑制 IC50 为 0.23 nM。对于 ，在 KYSE-520 异种移植模型的小鼠中，每日口服 1.0 mg/kg 的剂量足以实现 95%的 TGI。 在动物模型中具有良好的耐受性，并且在血浆浓度与肿瘤中 p-ERK 抑制之间观察到密切相关。目前， 正在作为一种潜在的抗癌药物进行临床试验。
