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Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing.

Abstract：

:The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Li Z,Powell CE,Groendyke BJ,Gero TW,Feru F,Feutrill J,Chen B,Li B,Szabo H,Gray NS,Scott DA

doi

10.1016/j.bmcl.2020.127456

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

127456

issue

19

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30567-9

journal_volume

30

pub_type

杂志文章

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