Synthesis and Comparative Study of a Library of Small Molecules Capable of Disrupting HIF2α Dimerization
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The concept of fighting cancer growth with anti-angiogenesis treatment is not new. Currently, Bevacizumab, anti-VEGF antibody, is used in some chemotherapeutic regiments. However, this is limited in that it is specific for only those cells that rely on VEGF. Thus, a need for treatments targeting different angiogenesis pathways has grown. In the past, it has been shown that tetrazolamine derivatives are capable of inhibiting the dimerization of HIF-2α, an important molecular target in the pathway of neovascularization both aberrantly and overly expressed in different cancer cell lines such as certain neuroendocrine tumors. Using the molecular scaffolding of tetrazolamine ring as a base, 24 different derivatives were synthesized and tested to determine an efficacious inhibitor of HIF-2α in terms of Kd and IC50 using Alphascreen and isothermal calorimetry techniques, respectively, after enantiomeric separation. In addition, molecular specificity was demonstrated in vitro for a pair of enantiomers by exposing cells in hypoxic environments to this drug and monitoring its effects on HIF1α and HIF2α pathway regulation. This study, firstly, is a stepping stone for the determination of higher potency compounds targeting HIF2α transcription factor with high selectively, and, secondly, more clearly defines the shape of the molecular binding site in the HIF2α transcription factor and, finally, opens up areas of further research in this family of compounds for biologic studies.