Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase

被引：4

作者：

Tichenor, Mark S. ^{[1
]}

Wiener, John J. M. ^{[1
,2
]}

Rao, Navin L. ^{[1
]}

Bacani, Genesis M. ^{[1
]}

Wei, Jianmei ^{[1
]}

Deckhut, Charlotte Pooley ^{[1
]}

Barbay, J. Kent ^{[1
,3
]}

Kreutter, Kevin D. ^{[1
,4
]}

Chang, Leon ^{[1
]}

Clancy, Kathleen W. ^{[1
]}

Murrey, Heather E. ^{[1
,5
]}

Wang, Weixue ^{[1
,5
]}

Ahn, Kay ^{[1
,6
]}

Huber, Michael ^{[1
,7
]}

Rex, Elizabeth ^{[1
]}

Coe, Kevin J. ^{[1
]}

Wu, Jiejun ^{[1
,8
]}

Rui, Haopeng ^{[1
,9
]}

Sepassi, Kia ^{[1
]}

Gaudiano, Marcello ^{[10
]}

Bekkers, Mariette ^{[10
]}

Cornelissen, Ivo ^{[10
]}

Packman, Kathryn ^{[10
]}

Seierstad, Mark ^{[1
]}

Xiouras, Christos ^{[10
]}

Bembenek, Scott D. ^{[1
,11
]}

Alexander, Richard ^{[12
]}

Milligan, Cynthia ^{[12
]}

Balasubramanian, Sriram ^{[12
,13
]}

Lebsack, Alec D. ^{[1
]}

Venable, Jennifer D. ^{[1
]}

Philippar, Ulrike ^{[10
]}

Edwards, James P. ^{[1
,14
]}

Hirst, Gavin ^{[1
,15
]}

机构：

[1] Janssen Res & Dev LLC, San Diego, CA 92121 USA

[2] Lundbeck La Jolla Res Ctr Inc, 10835 Rd Cure, Suite 250, San Diego, CA 92121 USA

[3] 6311 Sunnybrook Rd, Flourtown, PA 19031 USA

[4] Empress Therapeut, 790 Mem Dr, Cambridge, MA 02139 USA

[5] Scorp Therapeut, 1 Winthrop Sq, Boston, MA 02110 USA

[6] Kojin Therapeut, One Kendall Sq, Bldg 200, Suite 001, Cambridge, MA 02139 USA

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

[8] 11383 Pacific Shores Way, San Diego, CA 92130 USA

[9] 1175 Xietu Rd, Shanghai 200032, Peoples R China

[10] Janssen Res & Dev, B-2340 Beerse, Belgium

[11] Denovicon Therapeut, 1130 Wall St 558, La Jolla, CA 92037 USA

[12] Janssen Res & Dev LLC, Spring House, PA 19477 USA

[13] 11394 Fairwind Court, San Diego, CA 92130 USA

[14] Samsara BioCapital, 628 Middlefield Rd, Palo Alto, CA 94301 USA

[15] Turning Point Therapeut, 10628 Sci Ctr Dr, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 21期

关键词：

NF-KAPPA-B; IRREVERSIBLE INHIBITORS; ACTIVATION;

D O I：

10.1021/acs.jmedchem.2c01026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fc gamma receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

引用

页码：14326 / 14336

页数：11

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