5WO4

JAK1 complexed with compound 28

Summary for 5WO4

• Entry DOI: 10.2210/pdb5wo4/pdb
• Descriptor: Tyrosine-protein kinase JAK1, 3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide (3 entities in total)
• Functional Keywords: protein tyrosine kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Endomembrane system; Peripheral membrane protein: P23458
• Total number of polymer chains: 2
• Total formula weight: 70244.81

Authors

Lesburg, C.A.,Patel, S.B. (deposition date: 2017-08-01, release date: 2017-12-06, Last modification date: 2024-11-20)

Primary citation

Siu, T.,Brubaker, J.,Fuller, P.,Torres, L.,Zeng, H.,Close, J.,Mampreian, D.M.,Shi, F.,Liu, D.,Fradera, X.,Johnson, K.,Bays, N.,Kadic, E.,He, F.,Goldenblatt, P.,Shaffer, L.,Patel, S.B.,Lesburg, C.A.,Alpert, C.,Dorosh, L.,Deshmukh, S.V.,Yu, H.,Klappenbach, J.,Elwood, F.,Dinsmore, C.J.,Fernandez, R.,Moy, L.,Young, J.R.
The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.
J. Med. Chem., 60:9676-9690, 2017

PubMed Abstract: 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 Cl 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.

PubMed: 29156136
DOI: 10.1021/acs.jmedchem.7b01135

Experimental method

X-RAY DIFFRACTION (1.84 Å)