2. Academic Validation
  3. Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold

Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130344. doi: 10.1016/j.bmcl.2025.130344.
Xiaoyu Chen 1,  Xuepei Ma 2,  Zixuan Yang 2,  Mei Mao 2,  Wenjia Niu 2,  Chengwei Zhang 2,  Xiaolei Meng 2,  Mengjun Ma 3,  Zhuoyue Li 3,  Xiao Wang 3,  Shanshan Du 4,  Shumin Ma 5,  Siqi Zhang 6
Affiliations

Affiliations

  • 1 State Key Laboratory Base for Eco-Chemical Engineering in College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong 266042, China; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
  • 4 State Key Laboratory Base for Eco-Chemical Engineering in College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong 266042, China. Electronic address: shanshandu000@163.com.
  • 5 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China. Electronic address: mashumin@ouc.edu.cn.
  • 6 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China. Electronic address: zhangsiqi@baiyyy.com.cn.
PMID: 40701195 DOI: 10.1016/j.bmcl.2025.130344
Abstract

SOS1 plays a pivotal role in Ras activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, A15f and B5a emerged as the most potent compounds comparable to BI-3406. A15f and B5a exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in PERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced in vitro efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted Anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.

Keywords

Anti-proliferation activity; KRAS mutation; SOS1; Scaffold hopping.

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