Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression

Abstract

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC 50 ≤ 0.03 nM and D max > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3−3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer

“…Compared to other p300/CBP degraders 38,39,65 , including the CBPD-268 compound published by our group 65 , CBPD-409 is the only compound with good oral bioavailability and high target selectivity 35 , and CBPD-409 possesses better target degradation kinetics. CBPD-268 also has unintended activity against BRD family proteins 65 . Moreover, unlike the p300/CBP PROTAC targeting the HAT domain (JQAD1) 39 , bromodomain-binding p300/CBP PROTACs maintain the specificity and binding affinity of reader bromodomain inhibitors, thus also ensuring their strong on-target effects and safety.…”

“…As proof-of-concept, using related bromodomain inhibitor and PROTAC compounds (i.e., GNE-049 and CBPD-409), we demonstrate only p300/CBP degradation to completely extinguish its catalytic activity and trigger a potent growth inhibitory effect in several preclinical prostate cancer models. Compared to other p300/CBP degraders 38,39,65 , including the CBPD-268 compound published by our group 65 , CBPD-409 is the only compound with good oral bioavailability and high target selectivity 35 , and CBPD-409 possesses better target degradation kinetics. CBPD-268 also has unintended activity against BRD family proteins 65 .…”

“…To our knowledge, this is the first study that provides a mechanistic rationale for the development of p300/CBP degraders instead of the bromodomain inhibitors, which has direct implications for ongoing pharmacological and clinical efforts focused on targeting these enzymes in human cancers. Given the tolerability and more potent anti-tumor effects of CBPD-409, the recently developed p300/CBP PROTACs 35,65,68 could be powerful pharmacologic agents to treat enhancer-addicted cancers.…”

CBP/p300 Degrader: A Promising Therapeutic Strategy for Treatment of Prostate Cancer and Beyond

“…While potent CBP/p300 PROTAC degraders have been reported previously, none of them are orally active. − Therefore, designing orally active CBP/p300 degraders has been a challenging medicinal chemistry task that is meaningful for the purpose of clinical development. In their recent paper, Shaomeng Wang and co-workers report their work on the discovery of CBPD-268 as an exceptionally potent and orally efficacious CBP/p300 degrader …”

“…However, only a very small number of orally available CBP/p300 inhibitors have been developed for clinical research, underscoring the significant challenges associated with the development of CBP/p300-targeting drugs. In an article in this issue of the Journal of Medicinal Chemistry , Shaomeng Wang and co-workers report an exceptionally potent and orally efficacious CBP and p300 PROTAC degrader for the treatment of prostate cancer with excellent PK/PD properties …”