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

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

  • Eur J Med Chem. 2025 May 9:293:117752. doi: 10.1016/j.ejmech.2025.117752.
Mahmoud S Elkotamy 1,  Islam A Elkelesh 2,  Simone Giovannuzzi 3,  Rania S M Ismail 2,  Wessam M El-Refaie 4,  Abdulrahman A Almehizia 5,  Ahmed M Naglah 6,  Alessio Nocentini 3,  Claudiu T Supuran 3,  Mohamed Fares 7,  Hazem A Ghabbour 8,  Rofaida Salem 9,  Wagdy M Eldehna 9,  Hatem A Abdel-Aziz 10
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt. Electronic address: mahmoudelkotami@gmail.com.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Firenze, Italy.
  • 4 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Egypt.
  • 5 Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 6 Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. Electronic address: anaglah@ksu.edu.sa.
  • 7 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt; School of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 8 School of Health and Biomedical Sciences, RMIT University, Melbourne, 3083, Australia.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 10 Applied Organic Chemistry Department, National Research Center, Dokki, 12622, Cairo, Egypt. Electronic address: hatem_741@yahoo.com.
PMID: 40373635 DOI: 10.1016/j.ejmech.2025.117752
Abstract

Developing novel Anticancer agents that target critical pathways in non-small cell lung Cancer (NSCLC) presents a considerable challenge. This study synthesized 16 pyrazolo[1,5-a]pyrimidine derivatives with zinc-binding groups through molecular hybridization to achieve dual-target inhibition of tumor-associated Carbonic Anhydrase (CA) isoforms IX/XII and cyclin-dependent kinase 6 (CDK6). In-vitro assays indicated that sulfonamide-bearing compounds displayed enhanced CA inhibition, with compounds 7d, 11b, and 11d presenting Ki values of 11.2, 18.4, and 19.7 nM for CA IX, while compounds 11a and 11c exhibited Ki values of 14.8 and 8.7 nM for CA XII. Cytotoxicity assays conducted on NSCLC cell lines A549 and NCI-H1734 demonstrated that compounds 7c, 7d, 7i, and 11d exhibited superior activity relative to Roscovitine in both cell lines. While these compounds demonstrated limited inhibition of cyclin-dependent kinase 4 (CDK4), 7d and 11d effectively inhibited CDK6, with IC50 values of 0.054 and 0.069 μM, respectively, which are comparable to Palbociclib. Analyses of the cell cycle and Apoptosis demonstrated a strong G1 arrest and a notable induction of Apoptosis. Molecular docking confirmed essential binding interactions with CA IX/XII and CDK6, while in-silico ADMET predictions suggested favorable pharmacokinetics, despite potential toxicity concerns. Compounds 7d and 11d represent potential dual-target inhibitors for the treatment of NSCLC.

Keywords

CDK; Carbonic anhydrase; Molecular docking; NSCLC; Pyrazolo[1,5-a]pyrimidine.

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