First-in-Class Dual PDGFR/Carbonic Anhydrase IX/XII Inhibitors: 6,7-Dimethoxyquinoline-Sulfonamides as Promising Antileukemic Agents

  • J Med Chem. 2026 Feb 12;69(3):3115-3137. doi: 10.1021/acs.jmedchem.5c03037.
Eslam Roshdy  1  2 ,  Eva Řezníčková  3 ,  Mostafa M Elbadawi  4 ,  Ismail Celik  5 ,  Simone Giovannuzzi  6 ,  Denisa Veselá  3 ,  Veronika Vojáčková  3 ,  Petra Krňávková  3 ,  Alessio Nocentini  6 ,  Claudiu T Supuran  6 ,  Vladimír Kryštof  3 ,  Wagdy M Eldehna  4 ,  Manabu Abe  1  7
Affiliations
  • 1. Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
  • 2. Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 3. Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 77900 Olomouc, Czech Republic.
  • 4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey.
  • 6. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
  • 7. Research Center for Photo-Drug-Delivery Systems (Hi-PDDS), Hiroshima University, Higashi-Hiroshima 739-8526 Hiroshima, Japan.
PMID: 41587275 DOI: 10.1021/acs.jmedchem.5c03037
Abstract

Leukemia remains a challenging hematological malignancy, with limited therapeutic options. To address this unmet need, we report quinoline-sulfonamide hybrids as first-in-class dual inhibitors of platelet-derived growth factor receptor (PDGFR) and Carbonic Anhydrase (CA) IX/XII. Structure-activity relationship studies identified compound 9d as a potent lead, exhibiting strong inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (KI = 93.3 and 80.0 nM, respectively), along with exceptional antiproliferative activity in FIP1L1-PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents. Mechanistic analyses revealed that 9d effectively abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers Apoptosis. Molecular docking and 200 ns molecular dynamics simulations supported stable dual binding of 9d within the ATP-binding pocket of PDGFR and the catalytic cleft of CA IX. By simultaneously targeting oncogenic PDGFRA signaling and hypoxia-driven pH regulation (CA IX/XII), 9d represents a promising lead for preclinical development in PDGFR/CA IX/XII-driven leukemias.

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