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2025 PCF Challenge Award

Selective Proximity Targeting of AR and p300/CBP as a Therapeutic Strategy in Prostate Cancer

Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Shaomeng Wang, PhD (University of Michigan), YuanYuan Qiao, PhD (University of Michigan)

Co-Investigator: Mi Wang, PhD (University of Michigan)

Young Investigators: Jie Luo, PhD (University of Michigan), Jianzhang Yang, PhD (University of Michigan)

Description:

  • Prostate cancer is driven by oncogenic gene expression programs, characterized by altered transcription factors and epigenetic regulators, which are proteins that regulate DNA 3D structure and gene accessibility.
  • Notably, the epigenetic regulators p300 and CBP play pivotal roles in prostate cancer gene expression programs and have been identified as possible therapeutic targets.
  • In previous studies, drugs that degrade p300/CBP have shown promising activity in prostate cancer models and exhibit significant synergy when combined with androgen receptor (AR) inhibitors, underscoring the necessity of co-targeting AR and p300/CBP signaling.
  • Dr. Arul Chinnaiyan and team have developed a novel class of heterobifunctional drug: an AR-p300/CBP Domain ALTerAtion Chimera (DALTAC), that links an AR inhibitor to a p300/CBP bromodomain inhibitor (BRDi) via a custom-designed linker. This approach enforces a neomorphic AR–p300/CBP interaction that functionally disables the complex in a lineage-selective manner, with strongest activity in AR-positive prostate cancer cells.
  • This agent had significant promise in preclinical studies, and the team has since developed a new AR-p300/CBP DALTAC compound, with an improved pharmacokinetic profile and enhanced activity.
  • In this project, Dr. Chinnaiyan and team will define the unique mechanism of action of AR-p300/CBP DALTACs and evaluate their tumor suppressive efficacy through the following aims. This includes detailing the molecular impact of DALTACs on epigenetic and gene expression landscapes in various prostate cancer subtypes, optimizing the chemical structure of AR-p300/CBP DALTACs to enhance oral bioavailability and pharmacokinetic properties, and evaluating toxicities and therapeutic efficacy of AR-p300/CBP DALTACs in preclinical models of prostate cancer.
  • If successful, this project will establish AR-p300/CBP DALTACs as first-in-class heterobifunctional compounds that selectively target the AR-p300/CBP axis in prostate cancer cells through a novel mechanism and demonstrate the potential of this drug class as safe and effective targeted therapies for AR-driven metastatic prostate cancer, readying these for testing in clinical trials.

What this means to patients: Prostate cancer is driven by altered gene expression patterns, due to oncogenic activities of transcription factors such as the androgen receptor (AR) and epigenetic regulators including p300/CBP. In this project, Dr. Chinnaiyan and team have developed a first-in-class DALTAC drug that binds AR to p300/CBP, shutting down their activity through a novel mechanism, and will detail the mechanism of action, and formulate an optimal version with enhanced activity and pharmacokinetic properties, ready for clinical trials. This could lead to a new therapeutic option for lethal prostate cancer.