Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.
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.
Deciphera Pharmaceuticals, Lawrence, Kansas.
Bryan D
BD
Smith
Deciphera Pharmaceuticals, Lawrence, Kansas.
Michael D
MD
Kaufman
Deciphera Pharmaceuticals, Lawrence, Kansas.
Cynthia B
CB
Leary
Deciphera Pharmaceuticals, Lawrence, Kansas.
Benjamin A
BA
Turner
Deciphera Pharmaceuticals, Lawrence, Kansas.
Scott C
SC
Wise
Deciphera Pharmaceuticals, Lawrence, Kansas.
Yu Mi
YM
Ahn
Deciphera Pharmaceuticals, Lawrence, Kansas.
R John
RJ
Booth
Deciphera Pharmaceuticals, Lawrence, Kansas.
Timothy M
TM
Caldwell
Deciphera Pharmaceuticals, Lawrence, Kansas.
Carol L
CL
Ensinger
Deciphera Pharmaceuticals, Lawrence, Kansas.
Molly M
MM
Hood
Deciphera Pharmaceuticals, Lawrence, Kansas.
Wei-Ping
WP
Lu
Deciphera Pharmaceuticals, Lawrence, Kansas.
Tristan W
TW
Patt
Deciphera Pharmaceuticals, Lawrence, Kansas.
William C
WC
Patt
Deciphera Pharmaceuticals, Lawrence, Kansas.
Thomas J
TJ
Rutkoski
Deciphera Pharmaceuticals, Lawrence, Kansas.
Thiwanka
T
Samarakoon
Deciphera Pharmaceuticals, Lawrence, Kansas.
Hanumaiah
H
Telikepalli
Deciphera Pharmaceuticals, Lawrence, Kansas.
Lakshminarayana
L
Vogeti
Deciphera Pharmaceuticals, Lawrence, Kansas.
Subha
S
Vogeti
Deciphera Pharmaceuticals, Lawrence, Kansas.
Karen M
KM
Yates
Emerald Bio, Bainbridge Island, Washington.
Lawrence
L
Chun
Emerald Bio, Bainbridge Island, Washington.
Lance J
LJ
Stewart
Deciphera Pharmaceuticals, Lawrence, Kansas.
Michael
M
Clare
Deciphera Pharmaceuticals, Lawrence, Kansas. Deciphera Pharmaceuticals, Waltham, Massachusetts. dflynn@deciphera.com.
Daniel L
DL
Flynn
D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000068258:Bevacizumab / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008546:Melanoma, Experimental; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D059016:Tumor Microenvironment; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000813:Anilides; D000970:Antineoplastic Agents; C000597309:DCC-2701; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D000068258:Bevacizumab; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D048493:Proto-Oncogene Proteins B-raf