8V2F

Crystal structure of IRAK4 kinase domain with compound 9

Summary for 8V2F

• Entry DOI: 10.2210/pdb8v2f/pdb
• Related: 8V1O
• Descriptor: Interleukin-1 receptor-associated kinase 4, N-{2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: kinase important for immune response. protac design, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 151371.61

Authors

Weiss, M.M.,Zheng, X.,Browne, C.M.,Campbell, V.,Chen, D.,Enerson, B.,Fei, X.,Huang, X.,Klaus, C.R.,Li, H.,Mayo, M.,McDonald, A.A.,Paul, A.,Sharma, K.,Shi, Y.,Slavin, A.,Walter, D.M.,Yuan, K.,Zhang, Y.,Zhu, X.,Kelleher, J.,Ji, N.,Walker, D.,Mainolfi, N. (deposition date: 2023-11-22, release date: 2024-07-03, Last modification date: 2024-07-24)

Primary citation

Weiss, M.M.,Zheng, X.,Ji, N.,Browne, C.M.,Campbell, V.,Chen, D.,Enerson, B.,Fei, X.,Huang, X.,Klaus, C.R.,Li, H.,Mayo, M.,McDonald, A.A.,Paul, A.,Rong, H.,Sharma, K.,Shi, Y.,Slavin, A.,Walther, D.M.,Yuan, K.,Zhang, Y.,Zhu, X.,Kelleher, J.,Walker, D.,Mainolfi, N.
Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.
J.Med.Chem., 67:10548-10566, 2024

PubMed 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.

PubMed: 38920289
DOI: 10.1021/acs.jmedchem.3c01823

Experimental method

X-RAY DIFFRACTION (2.09 Å)