Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors

Xianming Deng; Jinhua Wang; Jianming Zhang; Taebo Sim; Nam Doo Kim; Takaaki Sasaki; William Luther; Rani E. George; Pasi A. Jänne; Nathanael S. Gray

doi:10.1021/ml200002a

Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors

Xianming Deng, Jinhua Wang, Jianming Zhang, Taebo Sim, Nam Doo Kim, Takaaki Sasaki, William Luther, Rani E. George, Pasi A. Jänne, Nathanael S. Gray

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC₅₀ values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

Original language	English
Pages (from-to)	379-384
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	2
Issue number	5
DOIs	https://doi.org/10.1021/ml200002a
Publication status	Published - 2011 May 12

Keywords

3,5-diamino-1,2,4-triazole urea
ALK

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1021/ml200002a

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title = "Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors",

abstract = "A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.",

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author = "Xianming Deng and Jinhua Wang and Jianming Zhang and Taebo Sim and Kim, {Nam Doo} and Takaaki Sasaki and William Luther and George, {Rani E.} and J{\"a}nne, {Pasi A.} and Gray, {Nathanael S.}",

year = "2011",

month = may,

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doi = "10.1021/ml200002a",

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volume = "2",

pages = "379--384",

journal = "ACS Medicinal Chemistry Letters",

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AU - Deng, Xianming

AU - Wang, Jinhua

AU - Zhang, Jianming

AU - Sim, Taebo

AU - Kim, Nam Doo

AU - Sasaki, Takaaki

AU - Luther, William

AU - George, Rani E.

AU - Jänne, Pasi A.

AU - Gray, Nathanael S.

PY - 2011/5/12

Y1 - 2011/5/12

N2 - A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

AB - A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

KW - 3,5-diamino-1,2,4-triazole urea

KW - ALK

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Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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