Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

被引：150

作者：

Powell, Chelsea E. ^{[1
,4
]}

Gao, Yang ^{[5
,6
]}

Tan, Li ^{[1
,4
]}

Donovan, Katherine A. ^{[1
,4
]}

Nowak, Radoslaw P. ^{[1
,4
]}

Loehr, Amanda ^{[5
,6
]}

Bahcall, Magda ^{[2
]}

Fischer, Eric S. ^{[1
,4
]}

Janne, Pasi A. ^{[2
,3
]}

George, Rani E. ^{[5
,6
]}

Gray, Nathanael S. ^{[1
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02215 USA

[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Pediat Hematol & Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

[6] Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02215 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 09期

基金：

美国国家卫生研究院;

关键词：

CELL LUNG-CANCER; INHIBITOR; RESISTANCE; POTENT;

D O I：

10.1021/acs.jmedchem.7b01655

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

引用

页码：4249 / 4255

页数：7

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