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

doi:10.1016/j.bmcl.2018.10.013

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. Epub 2018 Oct 11.

Authors

Min Jung Choi¹, Eun Joo Roh², Wooyoung Hur², So Ha Lee², Taebo Sim², Chang-Hyun Oh³, Sun-Hwa Lee⁴, Jong Seung Kim⁵, Kyung Ho Yoo⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amination
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Axl Receptor Tyrosine Kinase
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Isoindoles / chemical synthesis
Isoindoles / chemistry*
Isoindoles / pharmacology*
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism

Substances

Antineoplastic Agents
Isoindoles
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase
AXL protein, human