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 PMID: 29172502

ADC Targets in Oncology

2026-04-10

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

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 MyD88^L265P 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.