2. Academic Validation
  3. Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

  • J Med Chem. 2022 Nov 17. doi: 10.1021/acs.jmedchem.2c01517.
Silong Zhang 1 2,  Yu Zhang 1,  Xin Chen 3,  Juan Xu 2 4,  Huaxiang Fang 2,  Yuanyuan Li 3 2,  Yi Liu 1 3 5,  Huan He 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan430081, P. R. China.
  • 2 Wuhan Yuxiang Pharmaceutial Technology Co., Ltd., Wuhan430200, P. R. China.
  • 3 School of Life Science and Technology & School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan430023, P. R. China.
  • 4 College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi435003, P. R. China.
  • 5 State Key Laboratory of Membrane Separation and Membrane Process & Engineering Research Center of Precision Diagnosis and Treatment Technology and Equipment (MOE), School of Chemistry, Tiangong University, Tianjin300387, P. R. China.
PMID: 36384290 DOI: 10.1021/acs.jmedchem.2c01517
Abstract

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1-KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven Cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151881
    99.51%, SOS1抑制剂
    Ras
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