4mq1

The crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimidine inhibitorThe crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimidine inhibitor

Structural highlights

4mq1 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.35Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DYR1A_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]

Function

DYR1A_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 PubMed

DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.

Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.,Anderson K, Chen Y, Chen Z, Dominique R, Glenn K, He Y, Janson C, Luk KC, Lukacs C, Polonskaia A, Qiao Q, Railkar A, Rossman P, Sun H, Xiang Q, Vilenchik M, Wovkulich P, Zhang X Bioorg Med Chem Lett. 2013 Dec 15;23(24):6610-5. doi: 10.1016/j.bmcl.2013.10.055., Epub 2013 Nov 1. PMID:24239188^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x. PMID:21294719 doi:10.1111/j.1399-0004.2010.01544.x
↑ Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem Biophys Res Commun. 1996 Aug 5;225(1):92-9. PMID:8769099 doi:S0006-291X(96)91135-3
↑ Anderson K, Chen Y, Chen Z, Dominique R, Glenn K, He Y, Janson C, Luk KC, Lukacs C, Polonskaia A, Qiao Q, Railkar A, Rossman P, Sun H, Xiang Q, Vilenchik M, Wovkulich P, Zhang X. Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med Chem Lett. 2013 Dec 15;23(24):6610-5. doi: 10.1016/j.bmcl.2013.10.055., Epub 2013 Nov 1. PMID:24239188 doi:http://dx.doi.org/10.1016/j.bmcl.2013.10.055

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OCA

[1] van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x. PMID:21294719 doi:10.1111/j.1399-0004.2010.01544.x

[2] Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem Biophys Res Commun. 1996 Aug 5;225(1):92-9. PMID:8769099 doi:S0006-291X(96)91135-3

[3] Anderson K, Chen Y, Chen Z, Dominique R, Glenn K, He Y, Janson C, Luk KC, Lukacs C, Polonskaia A, Qiao Q, Railkar A, Rossman P, Sun H, Xiang Q, Vilenchik M, Wovkulich P, Zhang X. Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med Chem Lett. 2013 Dec 15;23(24):6610-5. doi: 10.1016/j.bmcl.2013.10.055., Epub 2013 Nov 1. PMID:24239188 doi:http://dx.doi.org/10.1016/j.bmcl.2013.10.055

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