5wal

From Proteopedia

(Difference between revisions)

Revision as of 20:18, 15 November 2017

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

Structural highlights

5wal is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	TYK2 (HUMAN)
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[TYK2_HUMAN] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.

Function

[TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.^[1]

Publication Abstract from PubMed

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.,Liang J, Van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair WS, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Goodacre S, Ghilardi N, MacLeod C, Johnson A, Bir Kohli P, Lai Y, Lin Z, Mantik P, Menghrajani K, Nguyen H, Peng I, Sambrone A, Shia S, Smith J, Sohn S, Tsui V, Ultsch M, Williams K, Wu LC, Yang W, Zhang B, Magnuson S Bioorg Med Chem Lett. 2017 Aug 12. pii: S0960-894X(17)30823-5. doi:, 10.1016/j.bmcl.2017.08.022. PMID:28830649^[2]

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

References

↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
↑ Liang J, Van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair WS, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Goodacre S, Ghilardi N, MacLeod C, Johnson A, Bir Kohli P, Lai Y, Lin Z, Mantik P, Menghrajani K, Nguyen H, Peng I, Sambrone A, Shia S, Smith J, Sohn S, Tsui V, Ultsch M, Williams K, Wu LC, Yang W, Zhang B, Magnuson S. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. Bioorg Med Chem Lett. 2017 Aug 12. pii: S0960-894X(17)30823-5. doi:, 10.1016/j.bmcl.2017.08.022. PMID:28830649 doi:http://dx.doi.org/10.1016/j.bmcl.2017.08.022

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wal"

@@ Line 3: / Line 3: @@
 <StructureSection load='5wal' size='340' side='right' caption='[[5wal]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wal]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WAL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WAL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wal]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WAL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WAL FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9ZS:N-[2-(2,6-dichlorophenyl)-1H-imidazo[4,5-c]pyridin-4-yl]cyclopropanecarboxamide'>9ZS</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wal FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wal OCA], [http://pdbe.org/5wal PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wal RCSB], [http://www.ebi.ac.uk/pdbsum/5wal PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wal ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Non-specific protein-tyrosine kinase]]
 [[Category: Magnuson, S]]

5wal

From Proteopedia

Revision as of 20:18, 15 November 2017

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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