Discovery of Pyrazoloquinazoline Analogues as Orally Bioavailable KRAS-G12D Inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• KRAS-G12D mutation is a key driver in 67.6% of pancreatic ductal adenocarcinoma (PDAC) cases.
• Development of selective KRAS-G12D inhibitors is crucial for targeted cancer therapy.

Purpose of the Study:

• To design, synthesize, and evaluate novel KRAS-G12D inhibitors.
• To identify a potent and orally bioavailable KRAS-G12D inhibitor for PDAC treatment.

Main Methods:

• Structure-based drug design utilizing pyrazoloquinazoline and ethylene-bridged piperazine pharmacophores.
• In vitro biochemical and cellular assays to assess binding affinity and activity.
• Pharmacokinetic and in vivo efficacy studies in a xenograft mouse model.

Main Results:

• Compound 53a demonstrated strong binding to KRAS-G12D (ΔTm = 12.1 °C) and potent in vitro activity (IC50s of 8.4 nM for p-ERK, 19.5 nM for AsPC-1 cell proliferation).
• Compound 53a exhibited improved oral bioavailability and favorable pharmacokinetic profiles compared to MRTX1133.
• Significant inhibition of tumor growth was observed in the AsPC-1 xenograft mouse model.

Conclusions:

• Compound 53a is a promising lead candidate for selective KRAS-G12D targeted cancer therapy.
• The developed inhibitors show potential for overcoming limitations of existing KRAS inhibitors, particularly in oral bioavailability.