Abstract：
Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essentially meaningful. Here, we identified an under-appreciated Serine/Threonine kinase, CDKL3 (Cyclin-dependent kinase like 3), crucially drives the rapid cell cycle progression and cell growth in cancers. Mechanism-wise, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate Retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of CDK4 by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 (Cyclin-dependent kinase 4/6) inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes the acquired resistance of the latter. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presented an integrated paradigm of cancer cell cycle regulation and suggested CDKL3-targeting as a feasible approach in cancer treatment.
摘要：
细胞周期调控在癌症中很大程度上是异常的。对异常细胞周期的分子理解和治疗靶向本质上是有意义的。这里,我们发现了一种低估的丝氨酸/苏氨酸激酶，CDKL3（细胞周期蛋白依赖性激酶样3），至关重要的是推动癌症中细胞周期的快速进展和细胞生长。机制方面，CDKL3定位于细胞核中，并与特异性细胞周期蛋白结合，直接磷酸化视网膜母细胞瘤（Rb）以退出静止状态。并行,CDKL3通过在T172上直接磷酸化以维持G1期进展来防止CDK4的泛素-蛋白酶体降解。CDKL3在癌症中的关键功能在体外和体内均得到证实。我们还设计了,合成并表征了一类CDKL3特异性抑制剂，HZ1.通过引起细胞周期停滞，HZ1在泛癌症治疗中表现出比CDK4/6（细胞周期蛋白依赖性激酶4/6）抑制剂更大的效力，并克服了后者的获得性抗性。特别是,CDKL3在结肠癌中具有显著的临床意义,小鼠和患者来源的癌症模型证明了HZ1的有效性。总的来说，这项工作提出了癌症细胞周期调控的综合范例,并建议CDKL3靶向作为癌症治疗的可行方法.
