Jiang Vivian, Xue Yu, Kim Hong, Cai Qingsong, Zhang Tianci, Nie Lei, McIntosh Joseph, Liu Yang, Chen Haiying, Zhou Jia, Wang Michael L
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
University of Texas Medical Branch, Galveston, Texas, United States.
Blood Adv. 2025 Jul 21. doi: 10.1182/bloodadvances.2025016511.
Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activity in vivo and showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Furthermore, YX0798 has the potential to be used in combination therapy with clinical agents to improve treatment efficacy. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.
非遗传转录进化已越来越多地被探索和认识到可驱动肿瘤细胞进展和治疗抗性。作为转录机制的调控枢纽，细胞周期蛋白依赖性激酶9（CDK9）是RNA聚合酶II（Pol II）转录的守门人，CDK9功能障碍会导致转录组重编程和肿瘤细胞进展。我们最近报道，HSP90-MYC-CDK9网络通过转录组重编程驱动套细胞淋巴瘤（MCL）的治疗抗性。我们还表明，在临床前MCL模型中，用AZD4573和enirociclib靶向CDK9是一种安全有效的治疗方法，支持CDK9作为MCL的有效治疗靶点。然而由于靶点选择性和口服生物利用度有限，目前正在进行治疗开发的CDK9抑制剂（CDK9i）仍有改进空间。为此，通过结构优化发现YX0798是一种新型CDK9i。YX0798在与CDK9结合时表现出显著的靶点选择性和高亲和力。此外，YX0798显示出良好的口服生物利用度。YX0798口服给药（5mg/kg，每日）时，在体内产生了有效的抗肿瘤活性，并显示出克服治疗抗性的效力。从机制上讲，YX0798下调短命癌蛋白c-MYC和促生存蛋白MCL-1是抑制CDK9的常见机制。此外，YX0798扰乱细胞周期并导致转录组重编程，最终导致细胞死亡。此外，YX0798有潜力与临床药物联合使用以提高治疗效果。总之，这些数据表明YX0798具有口服生物利用度、精确的选择性以及通过驱动转录重编程来杀死肿瘤细胞的抗肿瘤效力。
