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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
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01290
James S. Scott 1 , Sébastien L. Degorce 1 , Rana Anjum 2 , Janet Culshaw 3 , Robert D. M. Davies 3 , Nichola L. Davies 1 , Keith S. Dillman 2 , James E. Dowling 2 , Lisa Drew 2 , Andrew D. Ferguson 2 , Sam D. Groombridge 3 , Christopher T. Halsall 3 , Julian A. Hudson 3 , Scott Lamont 1 , Nicola A. Lindsay 1 , Stacey K. Marden 4 , Michele F. Mayo 2 , J. Elizabeth Pease 1 , David R. Perkins 3 , Jennifer H. Pink 3 , Graeme R. Robb 1 , Alan Rosen 2 , Minhui Shen 2 , Claire McWhirter 1 , Dedong Wu 4
Affiliation  

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.

中文翻译:

白介素1受体相关激酶4(IRAK4)的吡咯并嘧啶抑制剂的发现和优化,用于治疗突变型MYD88 L265P弥漫性大B细胞淋巴瘤。

本文中,我们报告了使用X射线晶体结构和基于结构的设计来鉴定和优化我们的支架,优化了一系列白介素1受体相关激酶4(IRAK4)的吡咯并嘧啶抑制剂。化合物28表现出良好的理化和激酶选择性,并被认为是一种有前途的体内工具,可利用该工具探索IRAK4抑制作用在突变MYD88 L265P弥漫性大B细胞淋巴瘤(DLBCL)的治疗中的作用。化合物28已显示在体​​外高浓度下具有抑制NF-κB活化和ABC亚型ABC亚型生长的能力,但与低浓度下的BTK抑制剂联用则显示出更大的作用。在体内,化合物28和依鲁替尼的组合在ABC-DLBCL小鼠模型中导致肿瘤消退。
更新日期:2017-12-11
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