S63845

S63845 is an excellent inhibitor with good potency and selectivity over other BCL2 family members (namely BCL2 and BCL-xL). It is active within mouse in vivo models at reasonable doses with no observable toxicity (note: mouse Mcl1 is significantly different than human MCL1, and many Mcl1 inhibitors do not target the mouse homolog (its not known if S63845 does or does not)). This agent should be considered the current best-in-class agent for targeting MCL1. A modest drawback is the need to utilize a IV route of administration for in vivo studies.

S63845 is a potent and selective MCL-1 inhibitor that is appropriate to use in cellular and in vivo studies. Based on its pharmacokinetic properties, S63845 cannot be dosed orally but requires intravenous dosing instead. Another drawback of this compound is its light sensitivity, which requires extra care in handling. Consistent with findings made for other MCL-1 inhibitors, S63845 has lower affinity to mouse MCL-1 than its human homolog (SPR data: Kd (human MCL-1) = 1.0 nM; Kd (mouse MCL-1) = 5.7 nM). Therefore, the target safety conclusions of the paper reporting this probe (Nature 2016, 538, 477–482), based on the fact that the compound is tolerated in mouse, need to be viewed with caution. Same as other described MCL-1 inhibitors, S63845 is difficult to synthesize and there is currently no robust supply source.

S63845 is a tool compound that was published in 2016 and apparently originated from an optimization program at Servier/WEHI leading to the clinical stage Mcl1 inhibitor S64315. Currently, the published data set for S63845 is broader than for the actual clinical compound. Therefore, it makes sense to use S63845 as a probe compound to study Mcl1 pharmacology. Several alternatives are available with AMG176 and AZD5991, however, all come from the same chemotype and it can therefore not be ruled out that all show related off-targets when used at unnecessarily high concentrations.

This probe is also very potent with many other cancer cell line tested, e.g. multiple myeloma derived and lymphoma cell line, as well as some patient, derived samples; No PK/PD relationship showed in the publication and thus somewhat limited its validity for in vivo use. Probe significantly increase MCL1 level in cell. Extremely slow off-rate in SPR data which might affect the accuracy of Kd reported.