Pre-clinical studies of gilteritinib, a next-generation FLT3 inhibitor

Lauren Y. Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C. Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small and Mark Levis


Activating mutations in the receptor tyrosine kinase FLT3 comprise approximately one-third of genetic lesions in acute myeloid leukemia (AML) and are associated with a poor prognosis. Internal tandem duplication (FLT3-ITD) mutations in particular are associated with a high relapse rate. Although FLT3 tyrosine kinase inhibitors (TKIs) appear to improve clinical outcomes for patients with FLT3-ITD AML, the development of early-generation FLT3 TKIs has been impeded by several obstacles such as low potency and selectivity, myelosuppression, and the emergence of resistance-conferring point mutations. Gilteritinib is a novel small molecule that potently inhibits FLT3 activity. We compared gilteritinib with 4 other TKIs currently in development (quizartinib, crenolanib, sorafenib, and midostaurin) using FLT3-mutated cell lines and primary patient samples. Our results indicate that gilteritinib overcomes many of the limitations of these other agents in that it has activity against tyrosine kinase domain (TKD) mutations and does not exhibit off-target activity against c-KIT. These features make gilteritinib potentially the most effective FLT3 TKI yet developed.

  • Submitted October 17, 2016.
  • Accepted November 29, 2016.