2 research outputs found
Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression
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
DC50 ≤ 0.03 nM and Dmax > 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
Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression
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
DC50 ≤ 0.03 nM and Dmax > 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