Design, Synthesis, and Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity for a Novel Series of 2,4,8,22-Tetraazatetracyclo[14.3.1.13,7.19,13]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene Macrocycles

被引：36

作者：

Breslin, Henry J. ^{[1
]}

Lane, Brandon M. ^{[1
]}

Ott, Gregory R. ^{[1
]}

Ghose, Arup K. ^{[1
]}

Angeles, Thelma S. ^{[1
]}

Albom, Mark S. ^{[1
]}

Cheng, Mangeng ^{[1
]}

Wan, Weihua ^{[1
]}

Haltiwanger, R. Curtis ^{[1
]}

Wells-Knecht, Kevin J. ^{[1
]}

Dorsey, Bruce D. ^{[1
]}

机构：

[1] Cephalon Inc, W Chester, PA 19380 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 01期

关键词：

EML4-ALK FUSION GENE; DRUG DISCOVERY; LUNG-CANCER; C-MET; IDENTIFICATION; PF-2341066; EFFICACY; RECEPTOR; GROWTH;

D O I：

10.1021/jm201333e

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

A novel set of 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles were prepared as potential anaplastic lymphoma kinase (ALK) inhibitors, designed to rigidly lock an energy-minimized bioactive conformation of the diaminopyrimidine (DAP) scaffold, a well-documented kinase platform. From 13 analogues prepared, macrocycle 2m showed the most promising in vitro ALK enzymatic (IC50 = 0.5 nM) and cellular (IC50 = 10 nM) activities. In addition, macrocycle 2m exhibited a favorable kinase selectivity preference for inhibition of ALK relative to the highly homologous insulin receptor (IR) kinase (IR/ALK ratio of 173). The inclusive in vitro biological results for this set of macrocycles validate this scaffold as a viable kinase template and further corroborate recent DAP/ALK solid state studies indicating that the inverted "U" shaped conformation of the acyclic DAPs is a preferred bioactive conformation.

引用

页码：449 / 464

页数：16

共 29 条

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