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 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.

中文翻译：

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发现 CBPD-268 是一种非常有效且口服有效的 CBP/p300 PROTAC 降解剂，能够实现肿瘤消退

CBP/p300 蛋白是关键的表观遗传调节因子，也是治疗去势抵抗性前列腺癌和其他类型人类癌症的有希望的靶点。在此，我们报告了 CBPD-268 的发现和表征，它是一种极其有效、有效且口服有效的 CBP/p300 蛋白 PROTAC 降解剂。 CBPD-268 在三种雄激素受体阳性前列腺癌细胞系中诱导 CBP/p300 降解，DC ₅₀ ≤ 0.03 nM 且D _max > 95%，从而导致有效的细胞生长抑制。它在小鼠和大鼠中具有优异的口服生物利用度。口服 0.3-3 mg/kg 的 CBPD-268 会导致肿瘤组织中 CBP/p300 深度持续减少，并在小鼠 VCaP 和 22Rv1 异种移植肿瘤模型中实现强抗肿瘤活性，包括 VCaP 肿瘤模型中的肿瘤消退。 CBPD-268 在小鼠和大鼠中具有良好的耐受性，并且显示治疗指数 >10。综合这些结果，CBPD-268 是一种非常有前景的 CBP/p300 降解剂，可作为潜在的新癌症疗法。