Singh Vinay Kumar, Justaud Frédéric, Brahmaiah Dabbugoddu, Kumar Nangunoori Sampath, Baratte Blandine, Robert Thomas, Bach Stéphane, Reddy Chada Raji, Levoin Nicolas, Grée René L
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France.
D.N.(P.G.) College, Khudwadhar, Gulaothi, Bulandshahr, Uttar Pradesh-203408, India.
Beilstein J Org Chem. 2025 Oct 24;21:2250-2259. doi: 10.3762/bjoc.21.172. eCollection 2025.
The cdc2-like kinases (CLKs), are a family of kinases that attracted recently the interest of scientists due to their significant biological roles, in particular in the regulation of the mRNA splicing process. Among the four isoforms of CLKs, CLK3 is the one for which the biological roles are less understood, in part because no selective inhibitor of this challenging kinase has been found to date. Based on structural analysis of the CLKs we have identified the lysine 241, present only in CLK3, as an attractive residue to design inhibitors with increased affinity towards this kinase as compared to the three other isoforms CLK1, CLK2, and CLK4. Based on this observation, we have been able to transform a molecule () previously established with a very low activity on CLK3 into a derivative which has now a significant affinity toward CLK3 (IC = 0.3 μM). Thus, appears as a new pan-inhibitor of the CLK family.
细胞周期蛋白依赖性激酶2样激酶（CLKs）是一类激酶，由于其重要的生物学作用，尤其是在mRNA剪接过程的调控中，最近引起了科学家们的关注。在CLKs的四种亚型中，CLK3的生物学作用了解较少，部分原因是迄今为止尚未发现针对这种具有挑战性的激酶的选择性抑制剂。基于对CLKs的结构分析，我们确定仅存在于CLK3中的赖氨酸241是一个有吸引力的残基，与其他三种亚型CLK1、CLK2和CLK4相比，可用于设计对该激酶具有更高亲和力的抑制剂。基于这一观察结果，我们能够将一种先前对CLK3活性非常低的分子（）转化为衍生物，该衍生物现在对CLK3具有显著的亲和力（IC = 0.3 μM）。因此，似乎是CLK家族的一种新型泛抑制剂。
