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2023 Igor Tulchinsky – PCF Young Investigator Award

A Novel CBP/p300 PROTAC Degrader Suppresses Prostate Cancer Progression via Re-Shaping the Chromatin Landscape and Acetylome

Jie Luo, PhD
University of Michigan

Mentors: Shaomeng Wang, Arul Chinnaiyan

Description:

  • CBP and p300 are proteins that regulate gene transcription and the 3D structure of the genome, and have been demonstrated as prostate cancer oncogenes and promising therapeutic targets in prostate cancer. However, most previously developed p300/CBP-inhibitors have performed poorly in prostate cancer clinical trials.
  • Jie Luo and team are developing a p300/CBP-targeted “PROTAC,” an emerging class of treatments that causes complete degradation of the protein target. This agent, named CBPD-409, appears highly promising in preclinical studies.
  • In this project, Dr. Luo will delineate the comprehensive roles of p300/CBP in prostate cancer and generate preclinical data on CBPD-409 to position it for clinical translation.
  • The effects of CBPD-409 treatment on the 3D genomic landscape and transcription factor activity in prostate cancer cells will be investigated. Results will be compared between CBPD-409 and other p300/CBP inhibitors to gain insights into their differential mechanisms of action.
  • Non-genomic, protein targets of p300/CBP activity will be identified and assessed for their role in prostate cancer.
  • The anti-tumor efficacy and biological effects of CBPD-409 alone and in combination with enzalutamide will be investigated in multiple preclinical prostate cancer models.
  • If successful, this project will define the full spectrum of the biological roles of p300/CBP in prostate cancer and generate preclinical data needed for the orally bioavailable PROTAC degrader, CBPD-409, which has potential to be quickly translated to early-phase clinical trials.

What this means to patients: p300/CBP is a promising therapeutic target for patients with advanced prostate cancer, yet prior drugs targeting these proteins have underperformed. Dr. Luo and team are developing a novel p300/CBP-degrading treatment, CBPD-409. This project will define the biological roles of p300/CBP in prostate cancer and provide preclinical data necessary for rapid translation of CBPD-409 into clinical trials.