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