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

Min Jung Choi, Eun Joo Roh, Wooyoung Hur, So Ha Lee, Taebo Sim, Chang Hyun Oh, Sun Hwa Lee, Jong Seung Kim, Kyung Ho Yoo

Research output: Contribution to journalArticle

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).

Original languageEnglish
JournalBioorganic and Medicinal Chemistry Letters
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Inhibitory Concentration 50
Phosphotransferases
Cells
Cell Line
Hinges
HeLa Cells
Acute Myeloid Leukemia
Scaffolds
Derivatives
Neoplasms
In Vitro Techniques
2-aminopyrimidine

Keywords

  • Aminopyrimidinylisoindolines
  • Antiproliferative activity
  • AXL kinase
  • Enzyme inhibitory activity
  • Inhibitors
  • TAM family

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors. / Choi, Min Jung; Roh, Eun Joo; Hur, Wooyoung; Lee, So Ha; Sim, Taebo; Oh, Chang Hyun; Lee, Sun Hwa; Kim, Jong Seung; Yoo, Kyung Ho.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journalArticle

Choi, Min Jung ; Roh, Eun Joo ; Hur, Wooyoung ; Lee, So Ha ; Sim, Taebo ; Oh, Chang Hyun ; Lee, Sun Hwa ; Kim, Jong Seung ; Yoo, Kyung Ho. / Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2018.
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