Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005

被引：4

作者：

Papa, Patrick ^{[1
]}

Whitefield, Brandon ^{[1
]}

Mortensen, Deborah S. ^{[1
]}

Cashion, Dan ^{[1
]}

Huang, Dehua ^{[1
]}

Torres, Eduardo ^{[1
]}

Parnes, Jason ^{[1
]}

Sapienza, John ^{[1
]}

Hansen, Joshua ^{[1
]}

Correa, Matthew ^{[1
]}

Delgado, Mercedes ^{[1
]}

Harris, Roy ^{[1
]}

Hegde, Sayee ^{[1
]}

Norris, Stephen ^{[1
]}

Bahmanyar, Sogole ^{[1
]}

Plantevin-Krenitsky, Veronique ^{[1
]}

Liu, Zheng ^{[1
]}

Leftheris, Katerina ^{[1
]}

Kulkarni, Ashutosh ^{[1
]}

Bennett, Brydon ^{[1
]}

Hur, Eun Mi ^{[2
]}

Ringheim, Garth ^{[2
]}

Khambatta, Godrej ^{[1
]}

Chan, Henry ^{[1
]}

Muir, Jeffrey ^{[1
]}

Blease, Kate ^{[1
]}

Burnett, Kelven ^{[1
]}

LeBrun, Laurie ^{[1
]}

Morrison, Lisa ^{[1
]}

Celeridad, Maria ^{[1
]}

Khattri, Roli ^{[1
]}

Cathers, Brian E. ^{[1
]}

机构：

[1] Bristol Myers Squibb, San Diego, CA 92121 USA

[2] Bristol Myers Squibb, Summit, NJ 07901 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 16期

关键词：

KAPPA-B ACTIVATION; PKC-THETA; OPTIMIZATION; AUTOIMMUNITY; AEB071; CELLS; MICE;

D O I：

10.1021/acs.jmedchem.1c00388

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The PKC-theta isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-theta inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.

引用

页码：11886 / 11903

页数：18

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