Development of small molecules targeting the pseudokinase Her3

被引：53

作者：

Lim, Sang Min ^{[1
,2
,3
]}

Xie, Ting ^{[1
,2
,3
]}

Westover, Kenneth D. ^{[4
,5
]}

Ficarro, Scott B. ^{[2
,6
,7
]}

Tae, Hyun Seop ^{[8
,9
]}

Gurbani, Deepak ^{[4
,5
]}

Sim, Taebo ^{[10
,11
]}

Marto, Jarrod A. ^{[2
,6
,7
]}

Jaenne, Pasi A. ^{[12
]}

Crews, Craig M. ^{[8
,9
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

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

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

[3] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA

[6] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA

[8] Yale Univ, Dept Chem, Dept Pharmacol, New Haven, CT 06511 USA

[9] Yale Univ, Dept Mol Cellular & Dev, New Haven, CT 06511 USA

[10] Korea Inst Sci & Technol, Chem Kinom Res Ctr, Seoul 136791, South Korea

[11] KU KIST Grad Sch Converging Sci & Technol, Seoul 136713, South Korea

[12] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 16期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

Her3; Pseudokinase; Hydrophobic tagging; Cancer; Pyrazolopyrimidine; TYROSINE KINASE; EXTENDED; 5-SUBSTITUENT; SELECTIVE INHIBITORS; LUNG-CANCER; PROTEIN; POTENT; DOMAIN; ERBB3; DEGRADATION; DISCOVERY;

D O I：

10.1016/j.bmcl.2015.04.103

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3382 / 3389

页数：8

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