Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gain-of-function mutations in RET (REarranged during Transfection) kinase are crucial oncogenic drivers in thyroid cancers, particularly Medullary Thyroid Carcinoma (MTC).
• Existing RET inhibitors are often ineffective against mutations within the enzyme's active site, such as V804L and V804M, limiting treatment options for MTC.

Purpose of the Study:

• To identify novel compounds targeting RET kinase, focusing on mutations within the active site that confer resistance to current therapies.
• To evaluate the efficacy and drug-like properties of a promising RET inhibitor identified through virtual screening.

Main Methods:

• Receptor-based virtual screening of the RET kinase domain was employed to identify potential inhibitors.
• In vitro assays were used to assess the inhibitory activity of the identified compound against wild-type and mutant RET kinase.
• Cell proliferation assays were performed using MTC cell lines and patient-derived tissues to evaluate anti-cancer effects.

Main Results:

• Compound 5 demonstrated efficient inhibition of both wild-type and V804L mutant RET kinase.
• Compound 5 significantly reduced the proliferation of MTC cell lines and patient-derived thyroid tissues.
• The compound exhibited favorable drug-like characteristics, suggesting potential for therapeutic development.

Conclusions:

• Compound 5 is a potent inhibitor of RET kinase, including clinically relevant mutations.
• This compound represents a promising therapeutic candidate for treating Medullary Thyroid Carcinoma, especially cases resistant to existing treatments.