Antagonizing the Androgen Receptor with a Biomimetic Acyltransferase

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• The Androgen Receptor (AR) is a key target in advanced prostate cancer treatment.
• Thiosalicylamide analogs function as acyltransferases, transferring acetate groups within cells.
• Existing therapies for advanced prostate cancer face limitations, necessitating novel approaches.

Purpose of the Study:

• To investigate redirecting the acyl-transfer activity of thiosalicylamides towards AR.
• To design and synthesize conjugates of thiosalicylamides with AR-binding ligands.
• To evaluate the efficacy of these conjugates in modulating AR function.

Main Methods:

• Conjugation of thiosalicylamides with tolfenamic acid, an AR-binding molecule.
• Treatment of CWR22Rv1 cells with the synthesized conjugate (YZ03).
• Analysis of endogenous AR acetylation and AR-coactivator peptide interactions.

Main Results:

• The thiosalicylamide-tolfenamic acid conjugate (YZ03) significantly enhanced AR acetylation in cells.
• Acetylation occurred at Lys720, a residue crucial for AR-coactivator binding.
• YZ03 improved the inhibition of AR-coactivator peptide association by AR-binding ligands.

Conclusions:

• Biomimetic acyltransferases can be engineered to target specific proteins like the Androgen Receptor.
• Covalent modification of critical interfacial residues can enhance the efficacy of protein-protein interaction inhibitors.
• This approach offers a promising strategy for developing novel therapeutics for advanced prostate cancer.