Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) treatment faces challenges with 20-40% of patients unresponsive to enzalutamide and abiraterone.
• Androgen receptor (AR) splice variants are implicated in primary resistance and secondary resistance to existing therapies.
• HDAC6 regulates AR activity by modulating Hsp90 acetylation, influencing AR localization and activation in both androgen-dependent and independent states.

Purpose of the Study:

• To design and synthesize novel dual-acting compounds targeting both the androgen receptor (AR) and HDAC6.
• To identify inhibitors effective for mCRPC patients resistant to current treatments.
• To evaluate the biological activity, specificity, and pharmacokinetic properties of these novel compounds.

Main Methods:

• Design and synthesis of dual-acting AR-HDAC6 inhibitors.
• In vitro evaluation of compound activity, including IC50 determination for HDAC6 inhibition and AR binding.
• Assessment of antagonist activity, cell-based effects, in vitro stability, and pharmacokinetic profiling.

Main Results:

• Successful identification of compound 10, a potent dual-acting inhibitor.
• Compound 10 exhibits strong dual activity with an HDAC6 IC50 of 0.0356μM and AR binding IC50 <0.03μM.
• Further evaluations demonstrated compound 10's antagonist properties, cell-based efficacy, stability, and favorable pharmacokinetic profile.

Conclusions:

• Dual-acting AR-HDAC6 inhibitors represent a promising therapeutic strategy for mCRPC.
• Compound 10 shows significant potential as a treatment option for patients with resistance to current therapies.
• Further development of compound 10 warrants investigation for clinical application in prostate cancer treatment.