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Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors.

Abstract：

:A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC50 values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC50 = <0.00050 μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC50 = <0.00050, 0.025, and 0.050 μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI50 = 0.10 μM) related to acute myeloid leukemia (AML).

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Choi MJ,Roh EJ,Hur W,Lee SH,Sim T,Oh CH,Lee SH,Kim JS,Yoo KH

doi

10.1016/j.bmcl.2018.10.013

subject

Has Abstract

pub_date

2018-12-15 00:00:00

pages

3761-3765

issue

23-24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30803-5

journal_volume

28

pub_type

杂志文章

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