Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors

  • Eur J Med Chem. 2024 Apr 15:270:116390. doi: 10.1016/j.ejmech.2024.116390.
Jiamin Zheng  1 ,  Zhisen Zhang  1 ,  Xiaoyu Ding  1 ,  Deheng Sun  1 ,  Lihua Min  1 ,  Feng Wang  1 ,  Sujing Shi  1 ,  Xin Cai  1 ,  Man Zhang  1 ,  Alex Aliper  2 ,  Feng Ren  1 ,  Xiao Ding  3 ,  Alex Zhavoronkov  4
Affiliations
  • 1. Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai, 201203, China.
  • 2. Insilico Medicine AI Limited, Masdar City, Abu Dhabi, 145748, United Arab Emirates.
  • 3. Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai, 201203, China. Electronic address: [email protected].
  • 4. Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai, 201203, China; Insilico Medicine AI Limited, Masdar City, Abu Dhabi, 145748, United Arab Emirates. Electronic address: [email protected].
PMID: 38604096 DOI: 10.1016/j.ejmech.2024.116390
Abstract

Protein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic. Here we report the design and development of compound 4, a novel small molecule PTPN2/N1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy.

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