College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Int J Mol Sci. 2023 Jan 31;24(3):2649. doi: 10.3390/ijms24032649.
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell receptor, which has been regarded as a potential target for immunotherapy. Yu et al. observed the off-target effect of the high-throughput screening HPK1 kinase inhibitor hits on JAK1 kinase. The off-target effect is usually due to the lack of specificity of the drug, resulting in toxic side effects. Therefore, exploring the mechanisms to selectively inhibit HPK1 is critical for developing effective and safe inhibitors. In this study, two indazole compounds as HPK1 inhibitors with different selectivity towards JAK1 were used to investigate the selectivity mechanism using multiple computational methods, including conventional molecular dynamics simulations, binding free energy calculations and umbrella sampling simulations. The results indicate that the salt bridge between the inhibitor and residue Asp101 of HPK1 favors their selectivity towards HPK1 over JAK1. Information obtained from this study can be used to discover and design more potent and selective HPK1 inhibitors for immunotherapy.
造血祖细胞激酶 1（HPK1）是 T 细胞受体的负调节剂，已被视为免疫治疗的潜在靶点。于等观察到高通量筛选 HPK1 激酶抑制剂对 JAK1 激酶的脱靶效应。脱靶效应通常是由于药物缺乏特异性，导致产生毒性副作用。因此，探索选择性抑制 HPK1 的机制对于开发有效和安全的抑制剂至关重要。在这项研究中，使用两种作为 HPK1 抑制剂的吲唑化合物，针对 JAK1 的选择性不同，使用多种计算方法，包括常规分子动力学模拟、结合自由能计算和伞状采样模拟，研究选择性机制。结果表明，抑制剂与 HPK1 的残基 Asp101 之间的盐桥有利于它们对 HPK1 的选择性高于 JAK1。从这项研究中获得的信息可用于发现和设计更有效和选择性的 HPK1 抑制剂用于免疫治疗。
