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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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