2. Academic Validation
  3. Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation

Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation

  • Bioorg Med Chem. 2022 Aug 1:67:116805. doi: 10.1016/j.bmc.2022.116805.
Bader I Huwaimel 1,  Sravan Jonnalagadda 2,  Shirisha Jonnalagadda 2,  Fatema T Zahra 3,  Alessio Nocentini 4,  Claudiu T Supuran 4,  Constantinos M Mikelis 5,  Paul C Trippier 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail, 81442, Saudi Arabia.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA.
  • 3 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
  • 4 Department NEUROFARBA - Pharmaceutical and nutraceutical section, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
  • 5 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Department of Pharmacy, University of Patras, Patras, 26504, Greece.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68106, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68106, USA; UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE 68106, USA. Electronic address: paul.trippier@unmc.edu.
PMID: 35635929 DOI: 10.1016/j.bmc.2022.116805
Abstract

Angiogenesis inhibitors are a critical pharmacological tool for the treatment of solid tumors. Suppressing vascular permeability leads to inhibition of tumor growth, invasion, and metastatic potential by blocking the supply of oxygen and nutrients. Disruption of the vascular endothelial growth factor (VEGF) signaling pathway is a validated target for the design of antiangiogenic agents. Several VEGFR2/KDR/Flk-1 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2/KDR/Flk-1 inhibitors highlighted key functional group overlap with the benzothiadiazine core contained in a library of in-house compounds. Herein we ascribe anti-angiogenic activity to a series of chlorinated benzothiadiazines. Selected compounds show significant activity to completely ameliorate VEGF-induced endothelial cell proliferation by suppression of VEGFR2/KDR/Flk-1 phosphorylation. The scaffold is devoid of activity to inhibit carbonic anhydrases and generally lacks cytotoxicity across a range of Cancer and non-malignant cell lines. Assay of activity at 468 kinases shows remarkable selectivity with only four kinases inhibited > 65% at 10 µM concentration, and with significant activity to inhibit TNK2/Ack1 and PKRD2 by > 90%. All four identified kinase targets are known modulators of angiogenesis, thus highlighting compound 17b as a novel angiogenesis inhibitor for further development.

Keywords

Angiogenesis; Kinase inhibitor; Mechanism of action; VEGFR2.

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