CPI-1205

This tool molecule adds another EZH2 inhibitor with slightly different biochemical potency and selectivity over the closely related EZH1. As such, the suite of tools provides an increasingly robust mechanism for starting to interrogate the pathway within cells. The observation that the molecules are competitive with SAM gives a rationale for the decrease in potency within the cellular context and the slow turnover of the substrate in cells could explain the slow onset of effects in vivo. Key data that is missing is a listing of the ~50 enzymes and transporters used for the broad out-of-family selectivity profiling. In addition, the lack of detail around the cellular data, particularly the Hill slope, limits the utility in translating from a cellular context to in vivo. A detailed PK profile is presented that could have been used to project how much inhibition is required to see a sustainable effect over a period of time, but this cannot be extrapolated as only the cellular IC₅₀ is presented. The in vivo efficacy data are less convincing than that for some of the other EZH2 inhibitors, but it is not clear whether this is due to different models or different profiles of the molecules, in terms of potency, cell penetration, or PK profile.

CPI-1205 is a Phase I/II agent designed to selectively target the EZH2  component of the polycomb repressor complex (PRC).  It is a well designed, and well described pharmacological tool with well defined pharmacokinetic properties.  The availability of several other probes, with differing chemotypes, against this target allows conformation of on-target pharmacology and CPI-1205 may be useful as a standalone agent, or for comparative pharmacology studies with probes such as EPZ-6438. It also offers a contrast to the EZH12 inhibitors such as GSK343 and EPZ011989. CPI-1205 inhibits methyltransferase activity through competition with SAM, and in doing so complements agents such as EED-226, which inhibits EZH2 activity by disrupting assembly of the polycomb repressor complex. Taken together, these two offer useful tools to dissect and understand some of the biology around the PRC, and the differential pharmacology between these complementary modes of action.