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Published on: June 30, 2023
Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation
Bader I Huwaimel1, Sravan Jonnalagadda2, Shirisha Jonnalagadda2
1Department 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.
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 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2 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 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.
Insights
New chlorinated benzothiadiazines show potent anti-angiogenic activity by inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. These compounds effectively reduce tumor cell proliferation without significant cytotoxicity, offering a promising avenue for cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Angiogenesis inhibitors are crucial for treating solid tumors by limiting nutrient and oxygen supply.
- The vascular endothelial growth factor (VEGF) signaling pathway, particularly VEGFR2, is a validated target for anti-angiogenic drug design.
- Structural similarities between approved VEGFR2 inhibitors and in-house benzothiadiazine compounds prompted further investigation.
Purpose of the Study:
- To investigate the anti-angiogenic potential of a series of chlorinated benzothiadiazines.
- To evaluate the mechanism of action and selectivity of these compounds.
- To identify novel angiogenesis inhibitors for cancer treatment.
Main Methods:
- Synthesis and screening of chlorinated benzothiadiazine derivatives.
- Assessment of inhibition of VEGF-induced endothelial cell proliferation and VEGFR2 phosphorylation.
- Evaluation of carbonic anhydrase inhibition and cytotoxicity across various cell lines.
- Kinase inhibition profiling to determine target selectivity.
Main Results:
- Several chlorinated benzothiadiazines demonstrated significant anti-angiogenic activity, effectively inhibiting VEGF-induced endothelial cell proliferation.
- Compounds suppressed VEGFR2 phosphorylation, indicating a targeted mechanism of action.
- The benzothiadiazine scaffold showed no significant carbonic anhydrase inhibition or cytotoxicity.
- Kinase assays revealed high selectivity, with potent inhibition of TNK2/ACK1 and PKRD2, kinases known to modulate angiogenesis.
Conclusions:
- Chlorinated benzothiadiazines represent a novel class of anti-angiogenic agents.
- Compound 17b, specifically, shows high efficacy and selectivity, targeting key kinases involved in angiogenesis.
- This scaffold warrants further development as a potential therapeutic agent for cancer treatment.
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