CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan–McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X‐ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high‐resolution X‐ray structures of all CLKs, including the first CLK4 X‐ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX‐4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan‐CLK inhibition in PMDS.

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Phelan–McDermid综合征的CLK2抑制剂的X射线结构和可行性评估

CLK2抑制被认为是改善Phelan–McDermid综合征（PMDS）的自闭症和神经元功能的潜在机制。本文报道了一个非常有效的吲唑CLK抑制剂系列的发现以及最有效的类似物的CLK2 X射线结构。该新的吲唑系列产品通过生化CLK2 Caliper分析筛查确定，其中包含通过计算机方法选择的30k化合物。还显示了所有CLK的新颖高分辨率X射线结构，包括与已知CLK2抑制剂工具化合物（例如TG003，CX-4945）绑定的第一个CLK4 X射线结构，并深入了解了CLK中的抑制剂选择性家庭。吲唑系列新型CLK2抑制剂的功效已在小鼠脑片测定中得到证实，并对潜在的安全性问题进行了研究。