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

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 journal › Article › peer-review

8 Citations (Scopus)

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 language	English
Pages (from-to)	3761-3765
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	23-24
DOIs	https://doi.org/10.1016/j.bmcl.2018.10.013
Publication status	Published - 2018 Dec 15

Bibliographical note

Funding Information:
This work was funded by the KIST Institutional Program (Grant No. 2E28010) from Korea Institute of Science and Technology, and by the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology ( CAP-17-01-KIST ).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

AXL kinase
Aminopyrimidinylisoindolines
Antiproliferative activity
Enzyme inhibitory activity
Inhibitors
TAM family

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2018.10.013

Cite this

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title = "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).",

keywords = "AXL kinase, Aminopyrimidinylisoindolines, Antiproliferative activity, Enzyme inhibitory activity, Inhibitors, TAM family",

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

note = "Funding Information: This work was funded by the KIST Institutional Program (Grant No. 2E28010) from Korea Institute of Science and Technology, and by the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology ( CAP-17-01-KIST ). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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doi = "10.1016/j.bmcl.2018.10.013",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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AU - Choi, Min Jung

AU - Roh, Eun Joo

AU - Hur, Wooyoung

AU - Lee, So Ha

AU - Sim, Taebo

AU - Oh, Chang Hyun

AU - Lee, Sun Hwa

AU - Kim, Jong Seung

AU - Yoo, Kyung Ho

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PY - 2018/12/15

Y1 - 2018/12/15

N2 - 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).

AB - 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).

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KW - Antiproliferative activity

KW - Enzyme inhibitory activity

KW - Inhibitors

KW - TAM family

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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