Identification of novel Pyrrolo[2,3-d]Pyrimidine-based KRAS G12C inhibitors with anticancer effects

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• The KRAS oncogene is a key driver in numerous human cancers, regulating critical cellular processes.
• Targeting the KRAS G12C mutation with covalent allosteric inhibitors is a promising therapeutic strategy.

Purpose of the Study:

• To design and synthesize novel pyrrolo[2,3-d]pyrimidine derivatives as KRAS G12C inhibitors.
• To evaluate the in vitro and in vivo anti-cancer efficacy of the synthesized compounds.

Main Methods:

• Systematic structural optimization of pyrrolo[2,3-d]pyrimidine derivatives.
• In vitro biochemical assays for KRAS/SOS1 inhibition and cancer cell proliferation.
• In vivo pharmacokinetic and anti-tumor efficacy studies.

Main Results:

• Compound 50, a novel pyrrolo[2,3-d]pyrimidine derivative, was identified with high KRAS/SOS1 inhibitory potency (IC50 = 0.21 μM).
• Compound 50 exhibited strong anti-proliferation activity against cancer cells with KRAS p.G12C mutation.
• The compound demonstrated satisfactory selectivity, moderate pharmacokinetics, and significant in vivo anti-cancer effects.

Conclusions:

• The study highlights the importance of conformational constraints in designing effective KRAS inhibitors.
• The developed compounds offer a novel scaffold and binding mechanism for targeting KRAS-driven cancers and overcoming drug resistance.