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Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma
Silong Zhang1,2, Yu Zhang1, Xin Chen3
1Key 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.
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.
Insights
A novel tetra-cyclic quinazoline derivative, compound 37, effectively inhibits the SOS1-KRAS interaction, showing promise for treating KRAS-driven cancers with improved drug exposure and half-life.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- KRAS mutations drive oncogenesis in refractory cancers.
- Son of sevenless homolog 1 (SOS1) is crucial for KRAS activation.
- Targeting the SOS1-KRAS interaction is a therapeutic strategy.
Purpose of the Study:
- To develop novel tetra-cyclic quinazoline derivatives as SOS1-KRAS inhibitors.
- To evaluate the efficacy and pharmacokinetic properties of compound 37.
- To assess the therapeutic potential of compound 37 in KRAS-driven cancers.
Main Methods:
- Synthesis of tetra-cyclic quinazoline derivatives.
- Pharmacokinetic studies in CD-1 mouse plasma.
- In vivo efficacy studies using Mia-paca-2 xenograft models.
- Preclinical safety assessment (CYP and hERG inhibition).
Main Results:
- Compound 37 demonstrated enhanced oral drug exposure and a longer half-life compared to BI-3406.
- Compound 37 alone inhibited tumor growth by 71% in a Mia-paca-2 xenograft model.
- Compound 37 exhibited limited inhibition of CYP and hERG enzymes.
Conclusions:
- Compound 37 is a potent inhibitor of the SOS1-KRAS interaction.
- Compound 37 possesses favorable pharmacokinetic properties and preclinical efficacy.
- Compound 37 represents a promising drug candidate for KRAS-driven cancers.
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