Rescuing the Function of Missense-Mutated Tumor Suppressor VHL using Stabilizing Small Molecules

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Somatic mutations and loss of heterozygosity in the VHL gene are key drivers of clear cell renal cell carcinoma (ccRCC).
• Mutations in the VHL gene can thermodynamically destabilize the pVHL protein, leading to loss of function.

Purpose of the Study:

• To identify small molecules that stabilize the folded conformation of mutant pVHL.
• To develop a therapeutic strategy for correcting destabilized VHL mutations in ccRCC.

Main Methods:

• Computational structure-based screening to identify potential stabilizing small molecules.
• Biophysical characterization and cellular assays to validate compound efficacy.
• Design and synthesis of CP4.29 as a lead stabilizing agent.

Main Results:

• Identified CP4.29, a small molecule that stabilizes the native folded structure of mutant pVHL.
• CP4.29 restores wild-type pVHL activities in cells harboring mutant VHL.
• Demonstrated the potential of stabilizing destabilized proteins for therapeutic benefit.

Conclusions:

• CP4.29 stabilizes mutant pVHL, restoring its function and offering a potential new class of kidney cancer drugs.
• The methodology may be applicable to developing treatments for other diseases caused by destabilized protein mutations.