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4i5c

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The Jak1 kinase domain in complex with inhibitor

Structural highlights

4i5c is a 2 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 2.1Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

JAK1_HUMAN Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.

Publication Abstract from PubMed

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.,Hurley CA, Blair WS, Bull RJ, Chang C, Crackett PH, Deshmukh G, Dyke HJ, Fong R, Ghilardi N, Gibbons P, Hewitt PR, Johnson A, Johnson T, Kenny JR, Kohli PB, Kulagowski JJ, Liimatta M, Lupardus PJ, Maxey RJ, Mendonca R, Narukulla R, Pulk R, Ubhayakar S, van Abbema A, Ward SI, Waszkowycz B, Zak M Bioorg Med Chem Lett. 2013 Jun 15;23(12):3592-8. doi: 10.1016/j.bmcl.2013.04.018., Epub 2013 Apr 17. PMID:23642482^[1]

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

References

↑ Hurley CA, Blair WS, Bull RJ, Chang C, Crackett PH, Deshmukh G, Dyke HJ, Fong R, Ghilardi N, Gibbons P, Hewitt PR, Johnson A, Johnson T, Kenny JR, Kohli PB, Kulagowski JJ, Liimatta M, Lupardus PJ, Maxey RJ, Mendonca R, Narukulla R, Pulk R, Ubhayakar S, van Abbema A, Ward SI, Waszkowycz B, Zak M. Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. Bioorg Med Chem Lett. 2013 Jun 15;23(12):3592-8. doi: 10.1016/j.bmcl.2013.04.018., Epub 2013 Apr 17. PMID:23642482 doi:10.1016/j.bmcl.2013.04.018