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Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents.

Abstract：

:Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Francis S,Croft D,Schüttelkopf AW,Parry C,Pugliese A,Cameron K,Claydon S,Drysdale M,Gardner C,Gohlke A,Goodwin G,Gray CH,Konczal J,McDonald L,Mezna M,Pannifer A,Paul NR,Machesky L,McKinnon H,Bower J

doi

10.1016/j.bmcl.2019.01.035

subject

Has Abstract

pub_date

2019-04-15 00:00:00

pages

1023-1029

issue

8

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30056-3

journal_volume

29

pub_type

杂志文章

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