Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165

被引：271

作者：

Wrobleski, Stephen T. ^{[1
]}

Moslin, Ryan ^{[1
]}

Lin, Shuqun ^{[1
]}

Zhang, Yanlei ^{[1
]}

Spergel, Steven ^{[1
]}

Kempson, James ^{[2
]}

Tokarski, John S. ^{[3
]}

Strnad, Joann ^{[4
]}

Zupa-Fernandez, Adriana ^{[4
]}

Cheng, Lihong ^{[4
]}

Shuster, David ^{[4
]}

Gillooly, Kathleen ^{[4
]}

Yang, Xiaoxia ^{[4
]}

Heimrich, Elizabeth ^{[4
]}

McIntyre, Kim W. ^{[4
]}

Chaudhry, Charu ^{[5
]}

Khan, Javed ^{[3
]}

Ruzanov, Max ^{[3
]}

Tredup, Jeffrey ^{[3
]}

Mulligan, Dawn ^{[3
]}

Xie, Dianlin ^{[3
]}

Sun, Huadong ^{[6
]}

Huang, Christine ^{[6
]}

D'Arienzo, Celia ^{[6
]}

Aranibar, Nelly ^{[6
]}

Chiney, Manoj ^{[6
]}

Chimalakonda, Anjaneya ^{[6
]}

Pitts, William J. ^{[1
]}

Lombardo, Louis ^{[1
]}

Carter, Percy H. ^{[1
]}

Burke, James R. ^{[4
]}

Weinstein, David S. ^{[1
,7
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Immunosci Discovery Chem, POB 4000, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Res & Dev, Dept Discovery Synth, POB 4000, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Res & Dev, Mol Struct & Design, Mol Discovery Technol, POB 4000, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Res & Dev, Immunosci Discovery Biol, POB 4000, Princeton, NJ 08543 USA

[5] Bristol Myers Squibb Res & Dev, Leads Discovery & Optimizat, POB 4000, Princeton, NJ 08543 USA

[6] Bristol Myers Squibb Res & Dev, Metab & Pharmacokinet Dept, Pharmaceut Candidate Optimizat, POB 4000, Princeton, NJ 08543 USA

[7] Vividion Therapeut Inc, 5820 Nancy Ridge Dr, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 20期

关键词：

ACTIVE RHEUMATOID-ARTHRITIS; FILGOTINIB GLPG0634/GS-6034; PSORIATIC-ARTHRITIS; PSEUDOKINASE DOMAIN; PLAQUE PSORIASIS; DOUBLE-BLIND; TOFACITINIB; MODERATE; IDENTIFICATION; EFFICACY;

D O I：

10.1021/acs.jmedchem.9b00444

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

引用

页码：8973 / 8995

页数：23

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