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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Leukemia is a challenging hematological malignancy with limited treatment options.
• Targeting both platelet-derived growth factor receptor (PDGFR) and carbonic anhydrase (CA) IX/XII presents a novel therapeutic strategy for leukemia.
• PDGFRA signaling and tumor-associated carbonic anhydrases (CA IX/XII) are implicated in certain leukemias.

Purpose of the Study:

• To develop novel quinoline-sulfonamide hybrids as dual inhibitors of PDGFR and CA IX/XII.
• To identify potent lead compounds for the treatment of PDGFR/CA IX/XII-driven leukemias.
• To investigate the mechanism of action of novel dual inhibitors.

Main Methods:

• Synthesis and structure-activity relationship (SAR) studies of quinoline-sulfonamide hybrids.
• Enzyme inhibition assays for PDGFR and CA IX/XII.
• Antiproliferative assays using leukemia cell lines (EOL-1).
• Mechanistic studies including cell-cycle analysis and apoptosis assays.
• Molecular docking and molecular dynamics simulations.

Main Results:

• Compound 9d demonstrated potent inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (Ki = 93.3 and 80.0 nM).
• Compound 9d exhibited significant antiproliferative activity in FIP1L1-PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents.
• Mechanistic studies showed that 9d abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers apoptosis.
• Molecular simulations confirmed stable dual binding of 9d to PDGFR and CA IX.

Conclusions:

• Quinoline-sulfonamide hybrids are effective dual inhibitors of PDGFR and CA IX/XII.
• Compound 9d is a potent lead compound with promising preclinical potential for PDGFR/CA IX/XII-driven leukemias.
• Simultaneous targeting of PDGFR and CA IX/XII offers a novel therapeutic approach for leukemia.