An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.

Abstract:

:A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.

journal_name

J Med Chem

authors

Colley HE,Muthana M,Danson SJ,Jackson LV,Brett ML,Harrison J,Coole SF,Mason DP,Jennings LR,Wong M,Tulasi V,Norman D,Lockey PM,Williams L,Dossetter AG,Griffen EJ,Thompson MJ

doi

10.1021/acs.jmedchem.5b01312

subject

Has Abstract

pub_date

2015-12-10 00:00:00

pages

9309-33

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

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