Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B‑Cell Lymphoma

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.