Marine-Inspired Spirooxindole PIM-1 Kinase Inhibitors Endowed with Concomitant TRKA/CDK2 Inhibition for Multifaceted Non-Small Cell Lung Cancer Apoptotic Induction.

Abstract

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 IC₅₀ 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 (IC₅₀ = 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.