三阴性乳腺癌（TNBC）是一种高度侵袭性、异质性和侵袭性的乳腺癌亚型，有效的治疗方式非常有限。通过蛋白水解靶向嵌合体 (PROTAC) 降解关键转录调节因子细胞周期蛋白依赖性激酶 9 (CDK9) 已显示出治疗 TNBC 的巨大潜力。然而，迄今为止，针对CDK9的PROTAC用于口服治疗癌症的报道尚未见报道。我们在此介绍了一系列新型 PROTAC 的设计、合成和广泛的生物学评估，这些 PROTAC 作为口服生物可利用的、有效的、选择性的 CDK9 降解剂，用于靶向三阴性乳腺癌的转录调节。开发的化合物 29 对 CDK9 降解表现出所需的效力 (DC50 = 3.94 nM) 和高效 (Dmax = 96%)，并有效抑制 TNBC MDA-MB-231 细胞的增殖。机理研究表明，化合物 29 是一种真正的 CDK9 降解剂，可以显着下调下游靶标 c-Myc 和 MCL-1。此外，化合物29在小鼠中表现出良好的口服生物利用度，口服降解剂29显着耗尽TNBC肿瘤组织中的CDK9蛋白，并在TNBC异种移植小鼠模型中表现出肿瘤生长抑制作用。总的来说，我们的工作表明，降解剂 29 是一种高效、选择性的 CDK9 降解剂，具有令人满意的口服生物利用度，在治疗 TNBC 方面具有广阔的前景。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous and invasive subtype of breast cancer with very limited effective modalities of treatment. Degrading the critical transcription regulator cyclin-dependent kinase 9 (CDK9) by proteolysis targeting chimeras (PROTACs) has shown promising potential for treating TNBC. However, to date, CDK9-targeting PROTACs for oral administration in treatment of cancers have not been reported. We herein present the design, synthesis, and extensive biological evaluation of a series of novel PROTACs as orally bioavailable, potent and selective degraders of CDK9 for targeting transcription regulation in triple-negative breast cancer. The developed compound 29 exhibited a desired potency (DC50 = 3.94 nM) with high efficacy (Dmax = 96 %) on CDK9 degradation, and effectively inhibited the proliferation of TNBC MDA-MB-231 cells. Mechanistic investigations revealed that compound 29 is a bona fide CDK9 degrader and can substantially downregulate the downstream targets c-Myc and MCL-1. Furthermore, compound 29 displayed favorable oral bioavailability in mice, and oral administration of degrader 29 significantly depleted CDK9 protein in TNBC tumor tissues and exhibited tumor growth inhibition in TNBC xenograft mice models. Collectively, our work established that degrader 29 is a highly potent and selective degraders of CDK9 with satisfactory oral bioavailability, which holds promising potential for the treatment of TNBC.Copyright © 2024 Elsevier Inc. All rights reserved.