Discovery of 3,5-diaryl-1H-pyrazol-based ureas as potent RET inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Rearranged during transfection (RET) is a key target in cancer therapy.
• Existing multikinase inhibitors (MKI) for RET-driven cancers have limitations.
• Novel RET inhibitors with enhanced selectivity and safety are needed.

Purpose of the Study:

• To discover and develop novel 3,5-diaryl-1H-pyrazol-based urea compounds as selective RET inhibitors.
• To evaluate the efficacy of these compounds against various RET mutations.
• To assess the pharmacokinetic properties and in vivo antitumor activity of lead compounds.

Main Methods:

• Synthesis and characterization of 3,5-diaryl-1H-pyrazol-based ureas.
• In vitro kinase inhibition assays against wild-type and mutant RET.
• Cellular assays using isogenic BaF3 cell lines with different RET alterations.
• Pharmacokinetic studies and in vivo antitumor efficacy evaluation in xenograft models.

Main Results:

• Compounds 17a/b exhibited high selectivity and potent inhibition of wild-type and V804M mutant RET.
• Moderate activity was observed against the G810C solvent-front mutation.
• Compound 17b displayed favorable pharmacokinetics and significant oral in vivo antitumor efficacy in a V804M xenograft model.

Conclusions:

• 3,5-diaryl-1H-pyrazol-based ureas represent a promising new class of RET inhibitors.
• Compound 17b is a potential lead candidate for further development in RET-driven cancers.
• These findings support the continued exploration of novel inhibitors targeting RET.