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

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

Matthew M. Weiss, Xiaozhang Zheng, Nan Ji, Chris M. Browne, Veronica Campbell, Dapeng Chen, Brad Enerson, Xue Fei, Xin Huang, Christine R. Klaus, Haoran Li, Michele Mayo, Alice A. McDonald, Atanu Paul, Haojing Rong, Kirti Sharma, Yatao Shi, Anthony Slavin, Dirk M. Walther, Karen Yuan, Yi Zhang, Xiao Zhu, Joe Kelleher, Duncan Walker, Nello Mainolfi

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.