Design, synthesis and biological evaluation of quinazoline SOS1 inhibitors

Bioorg Med Chem Lett. 2023 May 15:88:129265. doi: 10.1016/j.bmcl.2023.129265. Epub 2023 Apr 1.

Abstract

Son of sevenless 1 (SOS1) is a vital guanine nucleotide exchange factor (GEFs) that activates rat sarcoma (Ras) protein in cells. SOS1 inhibitors can effectively inhibit the expression of downstream signaling pathways by blocking the interaction between SOS1 and Ras protein. Here, we designed and synthesized a series of quinazoline-based compounds, and conducted subsequent evaluations of their biological activities. Among them, the comparable compounds I-2 (IC50 = 20 nM, against SOS1) I-5 (IC50 = 18 nM, against SOS1) and I-10 (IC50 = 8.5 nM, against SOS1) have kinase activity equivalent to BAY-293 (IC50 = 6.6 nM, against SOS1), and I-10 also has cell activity equivalent to BAY-293, providing a theoretical reference for subsequent related researches on SOS1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Guanine Nucleotide Exchange Factors / metabolism
  • Nuclear Family*
  • Phosphorylation
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Signal Transduction*
  • Son of Sevenless Proteins* / antagonists & inhibitors

Substances

  • Guanine Nucleotide Exchange Factors
  • Son of Sevenless Proteins
  • Quinazolines
  • BAY-293