Marine-Inspired Spirooxindole PIM-1 Kinase Inhibitors Endowed with Concomitant TRKA/CDK2 Inhibition for Multifaceted...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) management strategies often target apoptosis signaling pathways.
• Inhibiting PIM-1 and CDK2 kinases shows promise but has limited clinical success.
• Targeting TrkA is a recent focus for NSCLC, with FDA-approved drugs available.

Purpose of the Study:

• To design and synthesize novel hybrid ligands for simultaneous inhibition of PIM-1, CDK2, and TrkA.
• To evaluate the potential of these compounds as novel chemotherapeutics for NSCLC.

Main Methods:

• Synthesis of pyrazole-clubbed spirooxindoles via a one-pot [3+2] cycloaddition reaction.
• Structural confirmation using single-crystal X-ray diffraction and molecular electron density studies.
• In vitro evaluation of cytotoxicity using MTT assays against A549 NSCLC cells.
• In silico analysis including molecular docking and dynamics simulations.

Main Results:

• Several potent and selective inhibitors were identified, with IC50 values in the nanomolar range.
• Compounds 6e and 7f demonstrated balanced inhibition of PIM-1, CDK2, and TrkA.
• Compound 7f exhibited significant cytotoxicity, cell cycle disruption, and induced apoptosis in A549 cells.
• Molecular simulations elucidated key interactions responsible for compound binding and stability.

Conclusions:

• The synthesized spirooxindole derivatives represent a promising class of multi-targeted agents for NSCLC.
• Compound 7f is a potent cytotoxic agent with potential for further development as an anti-lung cancer chemotherapeutic.
• The study validates a multitargeting strategy involving PIM-1, CDK2, and TrkA inhibition for NSCLC therapy.