1.Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations.
Nishiyama U1, Yoshino T, Ozai M, Yoshioka R, Fujisawa M, Ogasawara Y, Kitahori M, Yoshioka E, Kubo K, Komeno Y, Kurokawa M, Ogawa S, Chiba S, Osawa T, Kuwaki T, Hirai H, Miwa A. Leuk Res. 2006 Dec;30(12):1541-6. Epub 2006 Apr 17.
Activating mutations of Fms-like tyrosine kinase 3 (Flt3) are the most common genetic abnormalities found in acute myeloid leukemia (AML) and represent potential therapeutic targets. The novel Flt3 inhibitor KRN383 inhibited the autophosphorylation of Flt3 bearing internal tandem duplications (ITDs) and the Asp835Tyr (D835Y) point mutation with half-maximal inhibitory concentration (IC(50)) values of < or =5.9 and 43 nM, respectively. KRN383 also inhibited the proliferation of the ITD-positive cell lines with IC(50) values of < or =2.9 nM. A single oral administration of 80 mg/kg of KRN383 eradicated ITD-positive xenograft tumors in nude mice and prolonged the survival of SCID mice carrying ITD-positive AML cells. The effectiveness of a single oral dose of KRN383 suggests that it has the potential to be used in a wide variety of clinical regimens, including multicycle and combination therapies.
2.FLT3 inhibitor KRN383 on xenografted human leukemic cells harboring FLT3-activating mutations FLT3 in AML: much more to learn about biology and optimal targeting.
Giles FJ. Leuk Res. 2006 Dec;30(12):1469-70. Epub 2006 May 2.
Aberrant FLT3 function in leukemia blasts is associated with a poor prognosis. A number of FLT3 modulators are in development. FLT3 mutations may synergistize with other molecular abnormalities in myeloid transformation. Further insights into FLT3 biology are needed to optimally study the therapeutic role of FLT3 inhibitors.