4AW5

Complex of the EphB4 kinase domain with an oxindole inhibitor

Summary for 4AW5

• Entry DOI: 10.2210/pdb4aw5/pdb
• Related: 2BBA 2VWU 2VWV 2VWW 2VWX 2VWY 2VWZ 2VX0 2VX1 2X9F 2XVD
• Descriptor: EPHRIN TYPE-B RECEPTOR 4, (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(5-methoxy-1H-benzimidazol-2-yl)(phenyl)methylidene]-1,3-dihydro-2H-indol-2-one (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P54760
• Total number of polymer chains: 1
• Total formula weight: 33390.37

Authors

Till, J.H.,Stout, T.J. (deposition date: 2012-05-31, release date: 2012-08-01, Last modification date: 2024-05-01)

Primary citation

Kim, M.H.,Tsuhako, A.L.,Co, E.W.,Aftab, D.T.,Bentzien, F.,Chen, J.,Cheng, W.,Engst, S.,Goon, L.,Klein, R.R.,Le, D.T.,Mac, M.,Parks, J.J.,Qian, F.,Rodriquez, M.,Stout, T.J.,Till, J.H.,Won, K.A.,Wu, X.,Michael Yakes, F.,Yu, P.,Zhang, W.,Zhao, Y.,Lamb, P.,Nuss, J.M.,Xu, W.
The Design, Synthesis, and Biological Evaluation of Potent Receptor Tyrosine Kinase Inhibitors.
Bioorg.Med.Chem.Lett., 22:4979-, 2012

PubMed Abstract: Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.

PubMed: 22765894
DOI: 10.1016/J.BMCL.2012.06.029

Experimental method

X-RAY DIFFRACTION (2.33 Å)