Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer

DOI

10.1016/j.bmc.2021.116061

Authors

Shruti Choudhary, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Arpit Doshi, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Lerin Luckett-Chastain, College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
Michael Ihnat, College of Pharmacy, University of Oklahoma Health Science Center, 1110 North Stonewall, Oklahoma City, OK 73117, United States.
Ernest Hamel, Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
Susan L. Mooberry, Department of Pharmacology, Mays Cancer Center, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
Aleem Gangjee, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.

Document Type

Journal Article

Publication Date

4-1-2021

Publication Title

Bioorganic & medicinal chemistry

Volume

35

First Page

116061

Keywords

Angiogenesis, Microtubule targeting agents, Multi-target inhibitors, Quinazolines, Receptor tyrosine kinase

Abstract

The efficacy of quinazoline-based antiglioma agents has been attributed to their effects on microtubule dynamics. The design, synthesis and biological evaluation of quinazolines as potent inhibitors of multiple intracellular targets, including microtubules and multiple RTKs, is described. In addition to the known ability of quinazolines 1 and 2 to cause microtubule depolymerization, they were found to be low nanomolar inhibitors of EGFR, VEGFR-2 and PDGFR-β. Low nanomolar inhibition of EGFR was observed for 1-3 and 9-10. Compounds 1 and 4 inhibited VEGFR-2 kinase with activity better than or equal to that of sunitinib. In addition, compounds 1 and 2 had similar potency to sunitinib in the CAM angiogenesis assay. Multitarget activities of compounds in the present study demonstrates that the quinazolines can affect multiple pathways and could lead to these agents having antitumor potential caused by their activity against multiple targets.

Open Access

Green Accepted

Preprint

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995636/

Repository Citation

Choudhary, S., Doshi, A., Luckett-Chastain, L., Ihnat, M., Hamel, E., Mooberry, S. L., & Gangjee, A. (2021). Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer. Bioorganic & medicinal chemistry, 35, 116061. https://doi.org/10.1016/j.bmc.2021.116061