4BBE

Aminoalkylpyrimidine Inhibitor Complexes with JAK2

Summary for 4BBE

• Entry DOI: 10.2210/pdb4bbe/pdb
• Related: 2B7A 2W1I 2XA4 4AQC 4BBF
• Descriptor: TYROSINE-PROTEIN KINASE JAK2, N-[4-[2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl]phenyl]ethanamide (3 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): O60674
• Total number of polymer chains: 4
• Total formula weight: 141537.88

Authors

Li, J. (deposition date: 2012-09-21, release date: 2012-11-21, Last modification date: 2024-05-01)

Primary citation

Forsyth, T.,Kearney, P.C.,Kim, B.G.,Johnson, H.W.B.,Aay, N.,Arcalas, A.,Brown, D.S.,Chan, V.,Chen, J.,Du, H.,Epshteyn, S.,Galan, A.A.,Huynh, T.P.,Ibrahim, M.A.,Kane, B.,Koltun, E.,Mann, G.,Meyr, L.E.,Lee, M.S.,Lewis, G.L.,Noguchi, R.T.,Pack, M.,Ridgway, B.H.,Shi, X.,Takeuchi, C.S.,Zu, P.,Leahy, J.W.,Nuss, J.M.,Aoyama, R.,Engst, S.,Gendreau, S.B.,Kassees, R.,Li, J.,Lin, S.-H.,Martini, J.-F.,Stout, T.,Tong, P.,Woolfrey, J.,Zhang, W.,Yu, P.
Sar and in Vivo Evaluation of 4-Aryl-2-Aminoalkylpyrimidines as Potent and Selective Janus Kinase 2 (Jak2) Inhibitors
Bioorg.Med.Chem.Lett., 22:7653-, 2012

PubMed Abstract: We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

PubMed: 23127890
DOI: 10.1016/J.BMCL.2012.10.007

Experimental method

X-RAY DIFFRACTION (1.9 Å)