9CUO

Crystal structure of CRBN with compound 3

This is a non-PDB format compatible entry.

Summary for 9CUO

• Entry DOI: 10.2210/pdb9cuo/pdb
• Descriptor: Protein cereblon, ZINC ION, (3S)-3-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidine-2,6-dione, ... (6 entities in total)
• Functional Keywords: crbn, e3, protein degradation, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 79190.35

Authors

Zheng, X.,Ji, N.,Campbell, V.,Slavin, A.,Zhu, X.,Chen, D.,Rong, H.,Enerson, B.,Mayo, M.,Sharma, K.,Browne, C.M.,Klaus, C.R.,Li, H.,Massa, G.,McDonald, A.A.,Shi, Y.,Sintchak, M.,Skouras, S.,Walther, D.M.,Yuan, K.,Zhang, Y.,Kelleher, J.,Guang, L.,Luo, X.,Mainolfi, N.,Weiss, M.M. (deposition date: 2024-07-26, release date: 2024-08-28, Last modification date: 2024-11-06)

Primary citation

Zheng, X.,Ji, N.,Campbell, V.,Slavin, A.,Zhu, X.,Chen, D.,Rong, H.,Enerson, B.,Mayo, M.,Sharma, K.,Browne, C.M.,Klaus, C.R.,Li, H.,Massa, G.,McDonald, A.A.,Shi, Y.,Sintchak, M.,Skouras, S.,Walther, D.M.,Yuan, K.,Zhang, Y.,Kelleher, J.,Liu, G.,Luo, X.,Mainolfi, N.,Weiss, M.M.
Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.
J.Med.Chem., 67:18022-18037, 2024

PubMed Abstract: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

PubMed: 39151120
DOI: 10.1021/acs.jmedchem.4c01305

Experimental method

X-RAY DIFFRACTION (1.6 Å)