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A novel small molecule inhibitor of Id proteins (AGX‐51) blocks cell survival in vitro and diminishes angiogenesis and tumor growth in vivo
Author(s) -
Chaudhary Jaideep,
Garland William,
Salvador Richard
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.761.4
Subject(s) - angiogenesis , in vivo , in silico , in vitro , cancer cell , cancer research , chemistry , small molecule , microbiology and biotechnology , matrigel , cell growth , apoptosis , cancer , biology , biochemistry , gene , genetics
The inhibitors of differentiation (Id) proteins (Id1, Id2, Id3, and Id4) are negative regulators of differentiation that act by sequestering basic helix loop helix (bHLH, e.g. E47) transcription factors. Ids are highly expressed during embryonic development but in adult tissues their expression is rare to absent. However, Id proteins are required for tumor angiogenesis and are also highly expressed in many cancer cells. As a proof of concept, decreased angiogenesis and tumor load as a result of blocking Id expression by antisense and siRNA molecules demonstrated that Id is a compelling anti‐cancer target. Based on a combination X‐ray crystal structure of Id1‐E47 interaction, in silico virtual screening and a high throughput electrophoretic mobility shift assay (EMSA), we discovered AGX‐51, a small molecule inhibitor of Id protein activity. In vivo and in vitro AGX‐51 disrupted Id1 and E47 interaction, blocked proliferation, induced apoptosis in cancer cell lines and significantly decreased neo‐vascularization in an in vivo matrigel plug assay. When used with Taxol, AGX‐51 also significantly decreased tumor growth by almost 50% compared to Taxol alone in nude mice implanted with MDA‐231 human breast cancer cells. In summary, a specific inhibitor of Id‐E47 interaction that has anti‐tumor activity is described for the first time. This research was supported by AngioGenex, Inc.