The Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Michigan Center for Translational Pathology, Department of Pathology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2024 Apr 11;67(7):5351-5372. doi: 10.1021/acs.jmedchem.3c01789. Epub 2024 Mar 26.
CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC 0.2-0.4 nM and displays strong antiproliferative effects with IC 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.
CBP/p300 是雄激素受体 (AR) 的关键转录共激活因子，是有前途的癌症治疗靶点。在此，我们报告了使用 PROTAC 技术发现高度有效、选择性和可口服生物利用的 CBP/p300 降解剂的情况，其中 CBPD-409 是最有前途的化合物。CBPD-409 以 DC 0.2-0.4 nM 的浓度诱导 CBP/p300 强烈降解，并在 VCaP、LNCaP 和 22Rv1 AR+前列腺癌细胞系中以 IC 1.2-2.0 nM 的浓度显示出强大的抗增殖作用。它具有良好的药代动力学特性，在小鼠中达到 50%的口服生物利用度。单次口服 1 mg/kg 的 CBPD-409 可使 VCaP 肿瘤组织中的 CBP/p300 蛋白减少 95%以上。CBPD-409 具有很强的肿瘤生长抑制作用，比两种 CBP/p300 抑制剂 CCS1477 和 GNE-049 以及 AR 拮抗剂恩扎鲁胺更有效、更有效。CBPD-409 是一种很有前途的 CBP/p300 降解剂，可进一步广泛评估用于治疗晚期前列腺癌和其他类型的人类癌症。
