| Structural highlights
Disease
CRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry.
Function
CRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2]
Publication Abstract from PubMed
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.
Discovery of KT-474 horizontal line a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.,Zheng X, Ji N, Campbell V, Slavin A, Zhu X, Chen D, Rong H, Enerson B, Mayo M, Sharma K, Browne CM, Klaus CR, Li H, Massa G, McDonald AA, Shi Y, Sintchak M, Skouras S, Walther DM, Yuan K, Zhang Y, Kelleher J, Liu G, Luo X, Mainolfi N, Weiss MM J Med Chem. 2024 Aug 16. doi: 10.1021/acs.jmedchem.4c01305. PMID:39151120[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM. Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics. 2008 Jul;9(3):219-23. doi: 10.1007/s10048-008-0128-2. Epub 2008, Apr 15. PMID:18414909 doi:http://dx.doi.org/10.1007/s10048-008-0128-2
- ↑ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. Identification of a primary target of thalidomide teratogenicity. Science. 2010 Mar 12;327(5971):1345-50. doi: 10.1126/science.1177319. PMID:20223979 doi:http://dx.doi.org/10.1126/science.1177319
- ↑ Zheng X, Ji N, Campbell V, Slavin A, Zhu X, Chen D, Rong H, Enerson B, Mayo M, Sharma K, Browne CM, Klaus CR, Li H, Massa G, McDonald AA, Shi Y, Sintchak M, Skouras S, Walther DM, Yuan K, Zhang Y, Kelleher J, Liu G, Luo X, Mainolfi N, Weiss MM. Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases. J Med Chem. 2024 Aug 16. PMID:39151120 doi:10.1021/acs.jmedchem.4c01305
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