Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma

被引：52

作者：

Scott, James S. ^{[1
]}

Degorce, Sebastien L. ^{[1
]}

Anjum, Rana ^{[2
]}

Culshaw, Janet

Davies, Robert D. M. ^{[3
]}

Davies, Nichola L. ^{[1
]}

Dillman, Keith S. ^{[2
]}

Dowling, James E. ^{[2
]}

Drew, Lisa ^{[2
]}

Ferguson, Andrew D. ^{[2
]}

Groombridge, Sam D. ^{[3
]}

Halsall, Christopher T. ^{[3
]}

Hudson, Julian A. ^{[3
]}

Lamont, Scott ^{[1
]}

Lindsay, Nicola A. ^{[1
]}

Marden, Stacey K. ^{[4
]}

Mayo, Michele F. ^{[2
]}

Pease, J. Elizabeth ^{[1
]}

Perkins, David R. ^{[3
]}

Pink, Jennifer H. ^{[3
]}

Robb, Graeme R. ^{[1
]}

Rosen, Alan ^{[2
]}

Shen, Minhui ^{[2
]}

McWhirter, Claire ^{[1
]}

Wu, Dedong ^{[4
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Oncol, Cambridge CB4 0FZ, England

[2] AstraZeneca, IMED Biotech Unit, Oncol, Boston, MA 02451 USA

[3] AstraZeneca, IMED Biotech Unit, Oncol, Macclesfield SK10 4TG, Cheshire, England

[4] AstraZeneca, IMED Biotech Unit, Pharmaceut Sci, Boston, MA 02451 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 24期

关键词：

PYOGENIC BACTERIAL-INFECTIONS; L265P SOMATIC MUTATION; PART; MYD88; SERIES; IDENTIFICATION; PREVALENCE; IBRUTINIB; HUMANS; POTENT;

D O I：

10.1021/acs.jmedchem.7b01290

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88(L265P) diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-kappa B activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.

引用

页码：10071 / 10091

页数：21

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