Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment

  • J Med Chem. 2024 Aug 22;67(16):13534-13549. doi: 10.1021/acs.jmedchem.4c00360.
Cunbo Ma  1 ,  Di Kang  2 ,  Panliang Gao  1 ,  Wei Zhang  3 ,  Xinping Wu  1 ,  Zilong Xu  1 ,  Huifeng Han  2 ,  Lei Zhang  2 ,  Yang Cai  2 ,  Yanping Wang  2 ,  Yinxiang Wang  2 ,  Wei Long  1
Affiliations
  • 1. Medicinal Chemistry, Jacobio Pharmaceuticals, Beijing 101111, China.
  • 2. Pharmacology, Jacobio Pharmaceuticals, Beijing 101111, China.
  • 3. Hits Discovery, Jacobio Pharmaceuticals, Beijing 101111, China.
PMID: 39110625 DOI: 10.1021/acs.jmedchem.4c00360
Abstract

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 Kd of 0.37 nM, SHP2 enzymatic IC50 of 1.9 nM, KYSE-520 antiproliferative IC50 of 7.4 nM and p-ERK inhibitory IC50 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.

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