TABLE 1

Summary of combination studies of EPZ-5676 with AML and ALL standard of care drugs and chromatin-modifying agents

Compounds were tested in combination with EPZ-5676 according to the cotreatment model described under Materials and Methods. The antiproliferative effect of the combinations in the MOLM-13 and MV4-11 cell lines was evaluated using the CalcuSyn software. In these studies, the lowest CI value obtained corresponding to a Fa value greater than 0.5 was used to assess the degree of synergism or antagonism as described in “Data Analysis.” For the SKM-1 cell line, the potency shift of the compound tested in the presence of EPZ-5676 was calculated from the dose response curves as described in “Data Analysis” and used to define the combination effect of the two drugs.

RationaleCompoundMOLM-13 (MLL-AF9)MV4-11 (MLL-AF4)SKM-1 (Non–MLL-r)
AML standard of careAra-CStrong synergyStrong synergyNo effecta
DaunorubicinSynergyStrong synergyNo effecta
DNA methyltransferase inhibitorsAzacitidineStrong synergySynergyNo effecta
DecitabineSynergySynergyNo effecta
Histone deacetylase inhibitorsVorinostatAdditive/synergyAntagonisticN/D
PanobinostatSynergyAntagonisticN/D
Demethylase inhibitorsTranylcypromineStrong synergySynergyNo effecta
LSD1 inhibitor IINearly additiveSynergyEnhancement
Bromodomain inhibitorsIBET-151SynergyStrong synergyNo effectb
JQ-1AdditiveAdditiveNo effecta
ALL standard of careMitoxantroneSynergySynergyNo effecta
MethotrexateAdditiveAdditivecNo effecta
MafosfamideStrong synergyStrong synergyNo effecta
PrednisoloneAntagonisticbAntagonisticbEnhancementb,d
VincristineAdditiveAdditiveNo effecta
  • IBET-151, 7-(3,5-dimethyl-4-isoxazolyl)-1,3-dihydroxy-8-methoxy-1-[(1R)-1-(2-pyridinyl)ethyl]-2H-imidazo[4,5-c]quinolin-2-one hydrochloride; N/D, not determined.

  • a No enhancement was observed based on analysis of the IC50 shift of the test compound in the presence of EPZ-5676. Analysis of IC50 shifts is described under Materials and Methods.

  • b IC50 of test compound not achieved.

  • c Methotrexate showed antagonistic effect in combination with EPZ-5676 at some constant ratios.

  • d Enhancement or shift in IC50 was observed at concentrations of EPZ-5676 of 2000 nM and above.