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

Luolong Qing; Zhengzai Cheng; Juan Xu; Ziwei Wang; Yuanyuan Li; Mario Gauthier; Silong Zhang; Huan He

doi:10.1016/j.ejmech.2024.117065

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. Epub 2024 Nov 17.

Authors

Luolong Qing¹, Zhengzai Cheng², Juan Xu³, Ziwei Wang¹, Yuanyuan Li⁴, Mario Gauthier⁵, Silong Zhang⁶, Huan He⁷

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.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Dynamics Simulation*
Molecular Structure
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
Proto-Oncogene Proteins p21(ras) / metabolism
Quinazolines* / chemical synthesis
Quinazolines* / chemistry
Quinazolines* / pharmacology
SOS1 Protein* / antagonists & inhibitors
SOS1 Protein* / metabolism
Structure-Activity Relationship

Substances

SOS1 Protein
Quinazolines
Antineoplastic Agents
SOS1 protein, human
Proto-Oncogene Proteins p21(ras)