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J Med Chem ; 67(13): 10548-10566, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38920289

ABSTRACT

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.


Subject(s)
Interleukin-1 Receptor-Associated Kinases , Lymphoma, Large B-Cell, Diffuse , Mutation , Myeloid Differentiation Factor 88 , Interleukin-1 Receptor-Associated Kinases/metabolism , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Myeloid Differentiation Factor 88/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Humans , Animals , Cell Line, Tumor , Drug Discovery , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Mice , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/metabolism , Proteolysis/drug effects , Structure-Activity Relationship
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