Tandutinib (MLN518)

Tandutinib (MLN518, CT53518) is a potent FLT3 antagonist with IC50 of 0.22 μM, also inhibits PDGFR and c-Kit, 15 to 20-fold higher potency for FLT3 versus CSF-1R and >100-fold selectivity for the same target versus FGFR, EGFR and KDR. IC50 value: 0.22 uM [1]Target: Flt3; PDGFRβ; c-Kitin vitro: Tandutinib has little activity against EGFR, FGFR, KDR, InsR, Src, Abl, PKC, PKA and MAPKs. Tandutinib inhibits IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. Tandutinib also inhibits the proliferation of human leukemia Ba/F3 cells containing FLT3-ITD mutations with IC50 values of 10-30 nM, and the FLT3-ITD-positive Molm-13 and Molm-14 cells with an IC50 of 10 nM. In FLT3-ITD-positive Molm-14 cells but not the FLT3-ITD-negative THP-1 cells, Tandutinib treatment leads to significant apoptosis by 51% and 78% at 24 and 96 hours, respectively, due to specific FLT3 inhibition [1]. Tandutinib preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, without affecting colony formation by normal human progenitor cells [2].in vivo: Oral administration of Tandutinib at 60 mg/kg bid significantly increases the survival in mice bearing Ba/F3 cells expressing W51 FLT3-ITD mutant, and gives a significant reduction in mortality in a mouse bone marrow transplantation model [1]. Tandutinib treatment at 180 mg/kg twice daily has mild toxicity toward normal hematopoiesis, however, it is a dose at which Tandutinib is effective in treating FLT3 ITD-positive leukemia in mice [2].

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> FLT3

Research Areas >> Cancer

[1]. Kelly LM, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell, 2002, 1(5), 421-432.

[2]. Griswold IJ, et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Blood, 2004, 104(9), 2912-2918.

[3]. Schittenhelm MM, et al. The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. Cell Cycle, 2009, 8(16), 2621-2630.

[4]. Salama Y, et al. The angiogenic factor Egfl7 alters thymogenesis by activating Flt3 signaling. Biochem Biophys Res Commun. 2017 Aug 19;490(2):209-216.

Gilteritinib | Quizartinib (AC220) | Pacritinib | Linifanib (ABT-869) | LY2784544 | DCC-2036 (Rebastinib) | Dovitinib (TKI-258, CHIR-258) | SB1317 | mrx-6313 | CHIR-124 | KW-2449 | ENMD-2076 | AST 487 | TG101209 | UNC-2371A