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

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.