Dapolsertib (SEL24-B489) is an orally bioavailable and potent PIM and FLT3-ITD inhibitor, inhibiting PIM1, PIM2, and PIM3, decreasing PIM substrate phosphorylation, and inducing dose-dependent apoptosis in leukemia cells.

Pim3:3 nM (Kd), Pim1:2 nM (Kd), Pim2:2 nM (Kd)

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 Dapolsertib, accompanied by PARP cleavage and apoptosis was observed [1] .
Dapolsertib causes a profound inhibition of S6 (S 235/236 ), but has little effect on PI3K/mTOR signaling [1] .
Dapolsertib inhibits STAT5 (Ser 726 ) and reduced expression of MCL1, whereas none of the selective inhibitors altered c-MYC abundance or induced PARP cleavage [1] .
Cell Viability Assay Cell Line: AZD1208, AC220 and AraC in AmL cell lines. Concentration: 0-10 μM. Incubation Time: 72 h. Result: Decreased viability.

Dapolsertib (25-100 mg/kg, orally) exhibited activity in AmL in vivo models [1] . Dapolsertib induces apoptosis of DLBCL cell lines in low/sub-micromolar concentrations and exhibits activity in a xenograft model [2] . Animal Model: SCID/beige mice bearing MV-4-11 tumors (FLT3-ITD+) [1] . 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).