6SM8

Human jak1 kinase domain in complex with inhibitor

Summary for 6SM8

• Entry DOI: 10.2210/pdb6sm8/pdb
• Descriptor: Tyrosine-protein kinase JAK1, 2-chloranyl-6-[(3~{S})-3-[(1~{S})-2-cyano-1-[4-(7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]ethyl]pyrrolidin-1-yl]benzenecarbonitrile, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: janus kinase 1 kinase domain (jak1), transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 70446.08

Authors

Read, J.A.,Steuber, H. (deposition date: 2019-08-21, release date: 2020-04-29, Last modification date: 2020-05-27)

Primary citation

Su, Q.,Banks, E.,Bebernitz, G.,Bell, K.,Borenstein, C.F.,Chen, H.,Chuaqui, C.E.,Deng, N.,Ferguson, A.D.,Kawatkar, S.,Grimster, N.P.,Ruston, L.,Lyne, P.D.,Read, J.A.,Peng, X.,Pei, X.,Fawell, S.,Tang, Z.,Throner, S.,Vasbinder, M.M.,Wang, H.,Winter-Holt, J.,Woessner, R.,Wu, A.,Yang, W.,Zinda, M.,Kettle, J.G.
Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.
J.Med.Chem., 63:4517-4527, 2020

PubMed Abstract: JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit to the candidate drug (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound has good preclinical pharmacokinetics. Compound displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.

PubMed: 32297743
DOI: 10.1021/acs.jmedchem.9b01392

Experimental method

X-RAY DIFFRACTION (1.85 Å)