2. Academic Validation
  3. Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

  • J Med Chem. 2022 Oct 13;65(19):13158-13171. doi: 10.1021/acs.jmedchem.2c00986.
Huan He 1 2,  Yu Zhang 1,  Juan Xu 3 2,  Yuanyuan Li 2 4,  Huaxiang Fang 2,  Yi Liu 1 4 5,  Silong Zhang 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Institute of Advanced Materials and Nanotechnology, Wuhan University of Science and Technology, Wuhan 430081, P. R. China.
  • 2 Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, P. R. China.
  • 3 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi 435003, P. R. China.
  • 4 School of Life Science and Technology & School Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, P. R. China.
  • 5 State Key Laboratory of Membrane Separation and Membrane Process & Tianjin Key Laboratory of Green Chemical Technology and Process Engineering, School of Chemistry, Tiangong University, Tianjin 300387, P. R. China.
PMID: 36173339 DOI: 10.1021/acs.jmedchem.2c00986
Abstract

The interaction between son of sevenless 1 (SOS1) gene and Kirsten rat sarcoma viral oncogene (KRAS) is crucial for activating signals of proliferation and survival in a range of cancers. We previously discovered compound 40a with a tetracyclic quinazoline pharmacophore as a potent orally bioavailable SOS1 inhibitor. Herein, we disclosed the discovery of compound 13c, which substituted the third ring with the seven-membered ring, as a clinical drug candidate for suppressing KRAS-driven tumors. 13c strongly disrupted the protein-protein interaction between SOS1 and KRAS with low IC50 values of 3.9 nM (biochemical) and 21 nM (cellular). 13c showed a favorable pharmacokinetic profile with a bioavailability of 86.8% in beagles and exhibited 83.0% tumor suppression in Mia-paca-2 pancreas xenograft mice tumor models. 13c exhibited a weak time-dependent CY3A4P inhibition than BI-3406, thereby reducing the risk of drug-drug interaction in drug combination. Toxicological investigations revealed that 13c had a lower risk of sudden cardiac death than BI-3406. Overall, 13c has been under evaluation in preclinical trials.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151517
    99.38%, SOS1 Inhibitor
    Ras