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
| Autor: | Keith Dillman, J. Elizabeth Pease, James E. Dowling, Nichola L. Davies, Rana Anjum, Robert D. M. Davies, Janet D. Culshaw, David R. Perkins, Dedong Wu, Julian A. Hudson, Sébastien L. Degorce, Jennifer H. Pink, Nicola Lindsay, Christopher Thomas Halsall, James S. Scott, Scott G. Lamont, Minhui Shen, Andrew D. Ferguson, Alan Rosen, Lisa Drew, Stacey Marden, Claire McWhirter, Sam D. Groombridge, Michele Mayo, Graeme R. Robb |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
biology Kinase Mutant medicine.disease IRAK4 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Biochemistry chemistry immune system diseases In vivo hemic and lymphatic diseases Ibrutinib Drug Discovery Cancer research medicine biology.protein Molecular Medicine Bruton's tyrosine kinase Receptor Diffuse large B-cell lymphoma |
| Zdroj: | Journal of Medicinal Chemistry. 60:10071-10091 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB 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. |
| Databáze: | OpenAIRE |
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