Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279

被引：35

作者：

Leit, Silvana ^{[1
]}

Greenwood, Jeremy ^{[2
]}

Carriero, Samantha ^{[1
]}

Mondal, Sayan ^{[2
]}

Abel, Robert ^{[2
]}

Ashwell, Mark ^{[1
]}

Blanchette, Heather ^{[1
]}

Boyles, Nicholas A. A. ^{[2
]}

Cartwright, Mark ^{[1
]}

Collis, Alan ^{[1
]}

Feng, Shulu ^{[2
]}

Ghanakota, Phani ^{[2
]}

Harriman, Geraldine C. C. ^{[1
]}

Hosagrahara, Vinayak ^{[1
]}

Kaila, Neelu ^{[1
]}

Kapeller, Rosanna ^{[1
]}

Rafi, Salma B. B. ^{[2
]}

Romero, Donna L. L. ^{[1
]}

Tarantino, Paul M. M. ^{[1
]}

Timaniya, Jignesh ^{[3
]}

Toms, Angela V. V. ^{[1
]}

Wester, Ronald T. T. ^{[1
]}

Westlin, William ^{[1
]}

Srivastava, Bhaskar ^{[1
]}

Miao, Wenyan ^{[1
]}

Tummino, Peter ^{[1
]}

McElwee, Joshua J. J. ^{[1
]}

Edmondson, Scott D. D. ^{[1
]}

Masse, Craig E. E. ^{[1
]}

机构：

[1] Nimbus Therapeut, Boston, MA 02210 USA

[2] Schrodinger Inc, New York, NY 10036 USA

[3] Piramal Pharm Solut, Ahmadabad 382215, Gujarat, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 15期

关键词：

PSEUDOKINASE-DOMAIN; DRUG DISCOVERY; TYK2; IDENTIFICATION; PREDICTION; EFFICACY; MODELS; POLARIZATION; DERIVATIVES; ACCURATE;

D O I：

10.1021/acs.jmedchem.3c00600

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

TYK2is a key mediator of IL12, IL23, and type I interferon signaling,and these cytokines have been implicated in the pathogenesis of multipleinflammatory and autoimmune diseases such as psoriasis, rheumatoidarthritis, lupus, and inflammatory bowel diseases. Supported by compellingdata from human genome-wide association studies and clinical results,TYK2 inhibition through small molecules is an attractive therapeuticstrategy to treat these diseases. Herein, we report the discoveryof a series of highly selective pseudokinase (Janus homology 2, JH2)domain inhibitors of TYK2 enzymatic activity. A computationally enableddesign strategy, including the use of FEP+, was instrumental in identifyinga pyrazolo-pyrimidine core. We highlight the utility of computationalphysics-based predictions used to optimize this series of moleculesto identify the development candidate 30, a potent, exquisitelyselective cellular TYK2 inhibitor that is currently in Phase 2 clinicaltrials for the treatment of psoriasis and psoriatic arthritis.

引用

页码：10473 / 10496

页数：24

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