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Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265PDiffuse Large B-Cell Lymphoma
- Source :
- Journal of Medicinal Chemistry; 20240101, Issue: Preprints
- Publication Year :
- 2024
-
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 28demonstrated 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 MYD88L265Pdiffuse large B-cell lymphoma (DLBCL). Compound 28was 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 28and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs44229815
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01290