3TJC

Co-crystal structure of jak2 with thienopyridine 8

Summary for 3TJC

• Entry DOI: 10.2210/pdb3tjc/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide (3 entities in total)
• Functional Keywords: jak2, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• Total number of polymer chains: 2
• Total formula weight: 70984.65

Authors

Huang, X. (deposition date: 2011-08-24, release date: 2011-11-30, Last modification date: 2024-10-16)

Primary citation

Schenkel, L.B.,Huang, X.,Cheng, A.,Deak, H.L.,Doherty, E.,Emkey, R.,Gu, Y.,Gunaydin, H.,Kim, J.L.,Lee, J.,Loberg, R.,Olivieri, P.,Pistillo, J.,Tang, J.,Wan, Q.,Wang, H.L.,Wang, S.W.,Wells, M.C.,Wu, B.,Yu, V.,Liu, L.,Geuns-Meyer, S.
Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors.
J.Med.Chem., 54:8440-8450, 2011

PubMed Abstract: Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.

PubMed: 22087750
DOI: 10.1021/jm200911r

Experimental method

X-RAY DIFFRACTION (2.4 Å)