STM2457

STM2457 is a best-in-class probe at present. I think it is great to use in cell assays since potency and binding are good and consistent with cellular thermal shift. The PK details are limited. It is difficult to understand in vivo use without knowing protein binding and really understanding how much free drug gets to site of action/target occupancy in vivo. A 50mpk dose is quite high so for in vivo use I see this as a molecule at the start of lead generation rather than a typical lead optimisation molecule which would ideally be <10mpk and be fully annotated with all PK parameters. At 50mpk, broader selectivity profiling beyond kinases (all target classes and toxicity panels e.g. ion channels) would be important.

STM2457 is a potent and selective probe with demonstrated on target cell activity. The compound was shown to be active against leukemia cell lines and leukemia PXD models.

Valuable first-in-class chemical probe. Robust characterization of specific target engagement is provided. Selectivity within narrow and broad enzyme families demonstrated. The compound is suitable for in vivo work with IP administration in mouse but note that detailed PK data were not provided. STM2120 is a useful but not ideal negative control – it is noticeably smaller than STM2457 and is missing a substituent making important lipophilic and polar interactions with the protein.