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Synthesis and evaluation of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives as Mnk inhibitors.

Abstract：

:Post-translational modulation of eIF4E through phosphorylation by Mnks is highly integral to the pathogenesis of different cancers. Therefore, inhibition of Mnks offers a strategy for cancer treatment. Herein, a series of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives is presented as Mnk inhibitors. Some of them showed sub-micromolar to low nanomolar inhibitory activities against Mnk1/2 with a high level of selectivity for both kinases over CDKs. Biochemical assays revealed that compounds 4c and 4t are non-ATP-competitive inhibitors of Mnks. Lead compound 4t demonstrated a high selectivity for Mnk1/2 over a selection of 51 kinases, and displayed anti-proliferative activities against a panel of cancer cell lines. However, this compound in combination with our in-house CDK4/6 inhibitor 83 did not show a synergistic effect in A2780 ovarian cancer cells, suggesting that caution be exercised in the selection of an agent to be combined with an Mnk inhibitor.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Abdelaziz AM,Basnet SKC,Islam S,Li M,Tadesse S,Albrecht H,Gerber C,Yu M,Wang S

doi

10.1016/j.bmcl.2019.07.043

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

2650-2654

issue

18

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30499-8

journal_volume

29

pub_type

杂志文章

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