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

Journal Article

2025

Published in: https://doi.org/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 þ 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.

• Publisher Name: Wiley-VCH GmbH
• Volume Number: 20
• Issue Number: 14