5wo4

JAK1 complexed with compound 28JAK1 complexed with compound 28

Structural highlights 5wo4 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 1.84Å 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 discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28. The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1 H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.,Siu T, Brubaker J, Fuller P, Torres L, Zeng H, Close J, Mampreian DM, Shi F, Liu D, Fradera X, Johnson K, Bays N, Kadic E, He F, Goldenblatt P, Shaffer L, Patel SB, Lesburg CA, Alpert C, Dorosh L, Deshmukh SV, Yu H, Klappenbach J, Elwood F, Dinsmore CJ, Fernandez R, Moy L, Young JR J Med Chem. 2017 Dec 4. doi: 10.1021/acs.jmedchem.7b01135. PMID:29156136 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Janus kinase 3D structures

spinqualitylabelsall models 5wo4, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image