Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
Comput Biol Med. 2024 Dec;183:109265. doi: 10.1016/j.compbiomed.2024.109265. Epub 2024 Oct 15.
A number of anaplastic lymphoma kinase (ALK) inhibitors have been clinically approved, with lorlatinib, particularly as a third-generation drug, demonstrating efficacy against various drug-resistant ALK single mutations. However, continued clinical use of lorlatinib has led to the emergence of ALK double mutations conferring resistance to lorlatinib, notably ALK. TPX-0131 is a potential fourth-generation ALK inhibitor currently under development. TPX-0131 demonstrates a broader spectrum of activity against ALK-resistant mutations, efficiently inhibiting 26 single-point mutations and various double/triple mutations, including solvent front mutations and gatekeeper mutations. In this study, for the first time, a comprehensive elucidation of the molecular mechanisms by which TPX-0131 overcomes lorlatinib resistance to ALK through modeling, MD simulations, free energy calculations, and US simulations. The results indicate that the interactions between lorlatinib and key residues at the hinge region are disturbed by L1196M/G1202R double mutation, leading to the disruption of important hydrogen bonding between Glu1197 and lorlatinib. For TPX-0131, the L1196M/G1202R mutation enhances electrostatic and van der Waals interactions, causing significant conformational changes primarily in the hinge region, G-loop, and β-strands. The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALK mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALK-induced NSCLC resistance and optimizing of ALK inhibitors.
已经有许多间变性淋巴瘤激酶（ALK）抑制剂在临床上得到了批准，洛拉替尼作为第三代药物，尤其对各种ALK 耐药单突变具有疗效。然而，洛拉替尼的持续临床应用导致了ALK 双突变的出现，这些突变对洛拉替尼产生了耐药性，特别是 ALK 的 TPX-0131 是一种潜在的第四代 ALK 抑制剂，目前正在开发中。TPX-0131 对 ALK 耐药突变具有更广泛的活性谱，能够有效抑制 26 个单点突变和各种双/三突变，包括溶剂前沿突变和守门员突变。在这项研究中，首次通过建模、MD 模拟、自由能计算和 US 模拟，全面阐述了 TPX-0131 克服 ALK 对洛拉替尼耐药性的分子机制。结果表明，L1196M/G1202R 双突变干扰了洛拉替尼与铰链区关键残基的相互作用，导致 Glu1197 与洛拉替尼之间重要氢键的破坏。对于 TPX-0131，L1196M/G1202R 突变增强了静电和范德华相互作用，导致主要在铰链区、G-环和 β-折叠中发生显著的构象变化。TPX-0131 与残基 Arg1202、Met1199 和 Arg1120 的紧密结合对克服 ALK 突变体中的洛拉替尼耐药性有很大贡献。这些研究结果有望为 TPX-0131 治疗 ALK 诱导的 NSCLC 耐药性和优化 ALK 抑制剂提供机制方面的见解。
