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From Proteopedia
Stat3 Core in complex with compound SD36
Structural highlights
Disease[STAT3_HUMAN] Chronic lymphoproliferative disorder of natural killer cells;Autosomal dominant hyper-IgE syndrome;STAT3-related early-onset multisystem autoimmune disease;T-cell large granular lymphocyte leukemia;Permanent neonatal diabetes mellitus. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[STAT3_HUMAN] Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).[UniProtKB:P42227][1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedSignal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo.,Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, Chen J, Yang CY, Liu Z, Wang M, Liu L, Jiang H, Wen B, Kumar P, Meagher JL, Sun D, Stuckey JA, Wang S Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002. PMID:31715132[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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