6s1i
Crystal Structure of DYRK1A with small molecule inhibitor
Structural highlights
DiseaseDYR1A_HUMAN Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.[1] FunctionDYR1A_HUMAN May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.[2] Publication Abstract from PubMedKinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining approximately 500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase beta (GSK3beta) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3beta/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor. Mining Public Domain Data to Develop Selective DYRK1A Inhibitors.,Henderson SH, Sorrell F, Bennett J, Hanley MT, Robinson S, Hopkins Navratilova I, Elkins JM, Ward SE ACS Med Chem Lett. 2020 Jun 30;11(8):1620-1626. doi:, 10.1021/acsmedchemlett.0c00279. eCollection 2020 Aug 13. PMID:32832032[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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