Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2

Autor: R. John Booth, Bryan D. Smith, Daniel L. Flynn, Lance Stewart, Tristan W. Patt, Scott C. Wise, Timothy M. Caldwell, Benjamin A. Turner, Molly M. Hood, Thomas J. Rutkoski, Wei-Ping Lu, Yu Mi Ahn, Michael Kaufman, Hanumaiah Telikepalli, Michael Clare, Subha Vogeti, Patt William Chester, Thiwanka Bandara Samarakoon, Karen M. Yates, Lakshminarayana Vogeti, Cynthia B. Leary, Lawrence Chun, Carol L. Ensinger
Rok vydání: 2015
Předmět:
Models
Molecular
Proto-Oncogene Proteins B-raf
Cancer Research
Angiogenesis
Melanoma
Experimental
Molecular Conformation
Aminopyridines
Antineoplastic Agents
Tumor initiation
Pharmacology
Biology
Monocytes
Metastasis
Inhibitory Concentration 50
Mice
Cell Movement
Cell Line
Tumor
Tumor Microenvironment
medicine
Animals
Humans
Anilides
Altiratinib
Protein Kinase Inhibitors
Cell Proliferation
Tumor microenvironment
Neovascularization
Pathologic
Hepatocyte Growth Factor
Kinase
Kinase insert domain receptor
Proto-Oncogene Proteins c-met
medicine.disease
Receptor
TIE-2
Vascular Endothelial Growth Factor Receptor-2
Xenograft Model Antitumor Assays
Recombinant Proteins
Bevacizumab
Disease Models
Animal
Oncology
Drug Resistance
Neoplasm
Drug Design
cardiovascular system
Cancer research
Drug Therapy
Combination
Female
Hepatocyte growth factor
Stromal Cells
medicine.drug
Zdroj: Molecular Cancer Therapeutics. 14:2023-2034
ISSN: 1538-8514
1535-7163
Popis: 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. Mol Cancer Ther; 14(9); 2023–34. ©2015 AACR.
Databáze: OpenAIRE
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