Al-Jassas Refaah M, Islam Mohammad Shahidul, Al-Majid Abdullah Mohammed, Haukka Matti, Nafie Mohamed S, Abu-Serie Marwa M, Teleb Mohamed, Shaaban Marwa M, Alayyaf Abdul Majeed Abdullah, Domingo Luis R, Ashraf Sajda, Ul-Haq Zaheer, Abdel Aziz Yasmine M, Barakat Assem
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451, Saudi Arabia.
Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014, Jyväskylä, Finland.
ChemMedChem. 2025 May 4:e2500028. doi: 10.1002/cmdc.202500028.
Several aspects of apoptosis signaling have been explored for managing non-small cell lung cancer (NSCLC). While inhibiting oncogenic kinases like PIM-1 and CDK2 has shown promise, clinical success remains limited. Recently, targeting TrkA gains attention following FDA approval of Entrectinib and Larotrectinib for NSCLC. In this study, a multitarget strategy is designed to simultaneously inhibit PIM-1, CDK2, and TrkA using hybrid ligands inspired by Saccharomonosporine A, a marine-derived oxindole-based metabolite. The hybrid scaffold incorporates spirooxindole derivatives with structural elements of CDK2 and TrkA inhibitors. A one-pot [3 + 2] cycloaddition reaction produces a series of pyrazole-clubbed spirooxindoles. Single-crystal X-ray diffraction and molecular electron density studies confirm product structures and propose reaction mechanisms. MTT assay against A549 NSCLC cells identifies compounds 6e, 6h, 7b, 7e, and 7f as potent and selective inhibitors, with IC values ranging from 0.022 to 0.098 μm and selectivity indices of 3.99-29.36. Compounds 6e and 7f emerge as the most balanced inhibitors of PIM-1 (IC = 3.9, 4.6 nm), CDK2, and TrkA. Molecular docking and dynamics simulations highlight key interactions stabilizing these compounds. 7f, the most potent cytotoxic spirooxindole derivative, disrupted the A549 cell cycle and induced apoptosis by 53-fold%. Accordingly, compound 7f can be further developed as anti-lung cancer chemotherapeutic with Trka/PIM-1/CDK2 inhibition pathway.
为了治疗非小细胞肺癌（NSCLC），人们已经对细胞凋亡信号传导的几个方面进行了探索。虽然抑制PIM-1和CDK2等致癌激酶已显示出前景，但临床成功仍然有限。最近，随着Entrectinib和Larotrectinib被FDA批准用于NSCLC，靶向TrkA受到关注。在本研究中，设计了一种多靶点策略，使用受海洋来源的基于氧化吲哚的代谢产物Saccharomonosporine A启发的杂合配体同时抑制PIM-1、CDK2和TrkA。杂合支架结合了螺环氧化吲哚衍生物以及CDK2和TrkA抑制剂的结构元素。一锅法[3 + 2]环加成反应产生了一系列吡唑连接的螺环氧化吲哚。单晶X射线衍射和分子电子密度研究证实了产物结构并提出了反应机制。针对A549 NSCLC细胞的MTT分析确定化合物6e、6h、7b、7e和7f为强效和选择性抑制剂，IC值范围为0.022至0.098μm，选择性指数为3.99 - 29.36。化合物6e和7f是PIM-1（IC = 3.9、4.6 nm）、CDK2和TrkA最均衡的抑制剂。分子对接和动力学模拟突出了稳定这些化合物的关键相互作用。7f是最有效的细胞毒性螺环氧化吲哚衍生物，破坏了A549细胞周期并诱导凋亡达53倍。因此，化合物7f可作为通过Trka/PIM-1/CDK2抑制途径的抗肺癌化疗药物进一步开发。
