SEL24-B489 is a potent, type I, orally active, dual PIM and FLT3-ITD inhibitor, with K d values of 2 nM for PIM1 , 2 nM for PIM2 and 3 nM for PIM3 , respectively
In Vitro
In MOLM-13 and to a lesser extent in MV4-11 cells, a dose-dependent disruption of cell cycle with especially pronounced depletion of the S phase after treatment with SEL24-B489, accompanied by PARP cleavage and apoptosis was observed. SEL24-B489 causes a profound inhibition of S6 (S 235/236 ), but has little effect on PI3K/mTOR signaling. SEL24-B489 inhibits STAT5 (Ser 726 ) and reduced expression of MCL1, whereas none of the selective inhibitors altered c-MYC abundance or induced PARP cleavage. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: AZD1208, AC220 and AraC in AML cell lines. Concentration: 0-10 μM. Incubation Time: 72 h. Result: Decreased viability.
In Vivo
SEL24-B489 (25-100 mg/kg, orally) exhibited activity in AML in vivo models . SEL24-B489 induces apoptosis of DLBCL cell lines in low/sub-micromolar concentrations and exhibits activity in a xenograft model. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: SCID/beige mice bearing MV-4-11 tumors (FLT3-ITD+) . Dosage: 50, 75 and 100 mg/kg. Administration: Orally, twice daily. Result: Marked dose – dependent tumor reduction (67%, 74% and 82% tumor growth inhibition (TGI) for 50, 75 and 100 mg/kg daily doses, respectively).
IC50& Target:PIM1 2 nM (Kd) PIM2 2 nM (Kd) PIM3 3 nM (Kd) FLT3-ITD
