2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

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

  • Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3761-3765. doi: 10.1016/j.bmcl.2018.10.013.
Min Jung Choi 1,  Eun Joo Roh 2,  Wooyoung Hur 2,  So Ha Lee 2,  Taebo Sim 2,  Chang-Hyun Oh 3,  Sun-Hwa Lee 4,  Jong Seung Kim 5,  Kyung Ho Yoo 6
Affiliations

Affiliations

  • 1 Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 02792, Republic of Korea.
  • 3 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 02792, Republic of Korea.
  • 4 Efficacy Assessment Support Department, New Drug Development Center, 80 Chembok-ro Dong-gu, Daegu 41061, Republic of Korea.
  • 5 Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
  • 6 Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 02792, Republic of Korea. Electronic address: khyoo@kist.re.kr.
PMID: 30340900 DOI: 10.1016/j.bmcl.2018.10.013
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).

Keywords

AXL kinase; Aminopyrimidinylisoindolines; Antiproliferative activity; Enzyme inhibitory activity; Inhibitors; TAM family.

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