title: Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors.
abstract: OBJECTIVE
  To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA.
  
  
  METHODS
  The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth.
  
  
  RESULTS
  Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC(50) of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency.
  
  
  CONCLUSIONS
  Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated.
authors: Portland VA Medical Center, Portland, OR, USA. Heinrich@ohsu.edu
authors: Michael C
authors: MC
authors: Heinrich
authors: Diana
authors: D
authors: Griffith
authors: Arin
authors: A
authors: McKinley
authors: Janice
authors: J
authors: Patterson
authors: Ajia
authors: A
authors: Presnell
authors: Abhijit
authors: A
authors: Ramachandran
authors: Maria
authors: M
authors: Debiec-Rychter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001562:Benzimidazoles / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001562:Benzimidazoles; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C577197:crenolanib