Rationally designed Pyrazolo[1,5-a]pyrimidines as dual inhibitors of CA IX/XII and CDK6: A novel approach for NSCLC...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) remains a significant therapeutic challenge.
• Targeting critical pathways like carbonic anhydrase (CA) isoforms IX/XII and cyclin-dependent kinase 6 (CDK6) offers potential for novel anticancer strategies.

Purpose of the Study:

• To synthesize and evaluate novel pyrazolo[1,5-a]pyrimidine derivatives as dual-target inhibitors of CA IX/XII and CDK6 for NSCLC treatment.
• To investigate the in-vitro anticancer activity, mechanism of action, and pharmacokinetic properties of these novel compounds.

Main Methods:

• Molecular hybridization was employed to design and synthesize 16 pyrazolo[1,5-a]pyrimidine derivatives incorporating zinc-binding groups.
• In-vitro assays included carbonic anhydrase inhibition, cytotoxicity against NSCLC cell lines (A549, NCI-H1734), kinase inhibition assays (CDK4, CDK6), cell cycle analysis, and apoptosis assays.
• Molecular docking and in-silico ADMET predictions were performed to assess binding interactions and pharmacokinetic profiles.

Main Results:

• Sulfonamide-containing derivatives showed potent inhibition of CA IX and CA XII, with specific compounds exhibiting nanomolar K_i values.
• Compounds 7c, 7d, 7i, and 11d demonstrated superior cytotoxicity against NSCLC cell lines compared to Roscovitine.
• Compounds 7d and 11d effectively inhibited CDK6 with IC₅₀ values comparable to Palbociclib, inducing G1 cell cycle arrest and apoptosis.

Conclusions:

• Compounds 7d and 11d are identified as promising dual-target inhibitors of CA IX/XII and CDK6 for NSCLC.
• These agents exhibit favorable in-vitro efficacy and potential for favorable pharmacokinetics, warranting further investigation for NSCLC therapy.