5DG5

CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HEPATOCYTE GROWTH FACTOR RECEPTOR C-MET IN COMPLEX WITH ALTIRATINIB ANALOG DP-4157

Summary for 5DG5

• Entry DOI: 10.2210/pdb5dg5/pdb
• Descriptor: Hepatocyte growth factor receptor, N-(2,5-difluoro-4-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxam ide (3 entities in total)
• Functional Keywords: tyrosine kinase domain, hepatocyte growth factor receptor c-met, c-met, altiratinib analog, dp-4157, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 2
• Total formula weight: 72996.19

Authors

Smith, B.D.,Kaufman, M.D.,Leary, C.B.,Turner, B.A.,Wise, S.A.,Ahn, Y.M.,Booth, R.J.,Caldwell, T.M.,Ensinger, C.L.,Hood, M.M.,Lu, W.-P.,Patt, T.W.,Patt, W.C.,Rutkoski, T.J.,Samarakoon, T.,Telikepalli, H.,Vogeti, L.,Vogeti, S.,Yates, K.M.,Chun, L.,Stewart, L.J.,Clare, M.,Flynn, D.L. (deposition date: 2015-08-27, release date: 2016-08-31, Last modification date: 2023-09-27)

Primary citation

Smith, B.D.,Kaufman, M.D.,Leary, C.B.,Turner, B.A.,Wise, S.C.,Ahn, Y.M.,Booth, R.J.,Caldwell, T.M.,Ensinger, C.L.,Hood, M.M.,Lu, W.P.,Patt, T.W.,Patt, W.C.,Rutkoski, T.J.,Samarakoon, T.,Telikepalli, H.,Vogeti, L.,Vogeti, S.,Yates, K.M.,Chun, L.,Stewart, L.J.,Clare, M.,Flynn, D.L.
Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.
Mol.Cancer Ther., 14:2023-2034, 2015

PubMed Abstract: Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.

PubMed: 26285778
DOI: 10.1158/1535-7163.MCT-14-1105

Experimental method

X-RAY DIFFRACTION (2.6 Å)