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  3. Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: A joint view of experiments and simulations

Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: A joint view of experiments and simulations

  • Eur J Med Chem. 2025 Jan 15:282:117065. doi: 10.1016/j.ejmech.2024.117065.
Luolong Qing 1,  Zhengzai Cheng 2,  Juan Xu 3,  Ziwei Wang 1,  Yuanyuan Li 4,  Mario Gauthier 5,  Silong Zhang 6,  Huan He 7
Affiliations

Affiliations

  • 1 Institute of Fine Organic Chemicals & Organic Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China.
  • 2 Institute of Fine Organic Chemicals & Organic Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China.
  • 3 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi, 435003, PR China.
  • 4 School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, PR China.
  • 5 Institute of Fine Organic Chemicals & Organic Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; Department of Chemistry, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
  • 6 Institute of Fine Organic Chemicals & Organic Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China. Electronic address: silongzhang@whu.edu.cn.
  • 7 Institute of Fine Organic Chemicals & Organic Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China; School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China. Electronic address: ivy@whu.edu.cn.
PMID: 39580914 DOI: 10.1016/j.ejmech.2024.117065
Abstract

Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of Cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC50 value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5 % inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.

Keywords

KRAS; Molecular dynamic simulations; Pancreas cancer; Quinazoline; SOS1.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168716
    SOS1-KRASG12C Inhibitor
    Ras