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:50
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
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
收藏
页码:10071 / 10091
页数:21
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