Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration.
Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration.
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DOI：
10.1021/acs.jmedchem.1c00440
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发表时间：
2022-01-27
影响因子：
7.3
通讯作者：
Axtman AD
中科院分区：
文献类型：
--
作者：
Drewry DH;Annor-Gyamfi JK;Wells CI;Pickett JE;Dederer V;Preuss F;Mathea S;Axtman AD
嘧啶核心已广泛用于构建激酶抑制剂，包括8种fda批准的药物。由于嘧啶铰链结合基序被许多人类激酶所容纳，因此所产生的分子的全激酶选择性可能很差。这种倾向被视为一种优势，因为它对许多未充分研究的激酶具有良好的耐受性。我们假设，未例证的氨基嘧啶带有侧链，这些侧链来自于对未充分研究的激酶具有脱靶活性的基于嘧啶的抑制剂，将为我们提供这些较少研究的激酶的有用抑制剂。我们的策略是将亲本化合物的2位和4位侧链与嘧啶核的5位修饰进行配对混合和匹配，嘧啶核位于结合袋的gatekeeper残基附近。利用这种方法，我们将改进的kinome-wide选择性赋予了结果库的大多数成员。重要的是，我们还发现了有效的生化和细胞活性先导化合物，用于未被研究的激酶，如DRAK1， BMP2K和MARK3/4。
The pyrimidine core has been utilized extensively to construct kinase inhibitors, including eight FDA-approved drugs. Because the pyrimidine hinge-binding motif is accommodated by many human kinases, kinome-wide selectivity of resultant molecules can be poor. This liability was seen as an advantage since it is well tolerated by many understudied kinases. We hypothesized that nonexemplified aminopyrimidines bearing side chains from well-annotated pyrimidine-based inhibitors with off-target activity on understudied kinases would provide us with useful inhibitors of these lesser studied kinases. Our strategy paired mixing and matching the side chains from the 2- and 4-positions of the parent compounds with modifications at the 5-position of the pyrimidine core, which is situated near the gatekeeper residue of the binding pocket. Utilizing this approach, we imparted improved kinome-wide selectivity to most members of the resultant library. Importantly, we also identified potent biochemical and cell-active lead compounds for understudied kinases like DRAK1, BMP2K, and MARK3/4.
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