2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Dec 28;60(24):10071-10091. 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
Affiliations

Affiliations

  • 1 Oncology, IMED Biotech Unit, AstraZeneca , Cambridge CB4 0FZ, United Kingdom.
  • 2 Oncology, IMED Biotech Unit, AstraZeneca , Boston, Massachusetts 02451, United States.
  • 3 Oncology, IMED Biotech Unit, AstraZeneca , Macclesfield SK10 4TG, United Kingdom.
  • 4 Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca , Boston, Massachusetts 02451, United States.
PMID: 29172502 DOI: 10.1021/acs.jmedchem.7b01290
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111101
    98.07%, IRAK4 Inhibitor