Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors

Clin Cancer Res. 2012 Aug 15;18(16):4375-84. doi: 10.1158/1078-0432.CCR-12-0625. Epub 2012 Jun 27.


Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA.

Experimental design: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzamides
  • Benzimidazoles / pharmacology*
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Activation / drug effects
  • Gastrointestinal Stromal Tumors / genetics*
  • Humans
  • Imatinib Mesylate
  • Inhibitory Concentration 50
  • Mutation*
  • Piperazines / pharmacology*
  • Piperidines
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology*
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*


  • Antineoplastic Agents
  • Benzamides
  • Benzimidazoles
  • Piperazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor alpha
  • crenolanib