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

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 (K_I = 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.