dcc-2701 and Disease-Models--Animal

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.

Topics: Aminopyridines; Anilides; Animals; Antineoplastic Agents; Bevacizumab; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Design; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Hepatocyte Growth Factor; Humans; Inhibitory Concentration 50; Melanoma, Experimental; Mice; Models, Molecular; Molecular Conformation; Monocytes; Neovascularization, Pathologic; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-met; Receptor, TIE-2; Recombinant Proteins; Stromal Cells; Tumor Microenvironment; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays