2. Academic Validation
  3. Discovery of novel substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors

Discovery of novel substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors

  • Eur J Med Chem. 2024 Sep 5:279:116830. doi: 10.1016/j.ejmech.2024.116830.
Xiashi Lv 1,  Peifeng Li 2,  Zhuo Chen 1,  Siting Huang 2,  Shuang Zhang 1,  Bei Ji 2,  Jingjing Liu 3,  Tonghong Du 1,  Tingting Zhang 2,  Xijing Chen 3,  Lei Qiang 4,  Yuan He 5,  Yisheng Lai 6
Affiliations

Affiliations

  • 1 Center for Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: lqiang@cpu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: yuanhe0822@cpu.edu.cn.
  • 6 Center for Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: yslai@cpu.edu.cn.
PMID: 39303516 DOI: 10.1016/j.ejmech.2024.116830
Abstract

Src homology-2-containing protein tyrosine Phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for Cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC50 values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206+/Ly6C+ M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80+/CD206+ M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 Inhibitor worthy of further development.

Keywords

Allosteric inhibitor; Antitumor efficacy; Molecular docking; Molecular dynamics simulation; Pyridine carboxamide derivative; SHP2.

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