CS640

The NanoBRET assay data that was shown in 'In Cell Validation 1' could not be identified in the reference. It might cause some problems that CS640 has the limited selectivity over other CAMK1s.

The probe CS640 is a highly potent inhibitor of CaMK1D, along with family members CaMK1B, CaMK1A, and CaMK1G (8, 3, 1, and 1 nM respectively). Because it is more potent on the CaMK isoforms than on CaMK1D itself, it cannot be used as a probe to differentiate from biological responses that result from inhibition of other 3 CaMK isoforms. Nonetheless, CS640 is highly selective against kinases outside of the CaMK family, and therefore it can be considered to be useful for evaluating the combined roles of this family of enzymes, particularly in view of its excellent (11 nM) cellular activity. Because no other compounds are available that target CaMK isoforms selectivity, CS640 is therefore the most useful probe for CaMK1D available. Outside of the kinase family, CS640 has some activity at hERG (3.7 uM) and CYP450 2C9 (6 uM). Importantly, CS640 has shown excellent rodent PK through the oral route of administration and has been found to be well-tolerated in mice upon repeat dosing at 40 mg/kg/day for 21 days. Interestingly, there is no in vivo activity data reported for CS640 although a closely related compound has shown in vivo activity in a mouse diabetic model at 10-15 mg/kg. Since the plasma protein binding data for CS640 is also not available, is unclear what is the optimal vivo dose. It is therefore suggested to use the reported rodent plasma PK and the recommended concentration (10 mg/kg) as a guide, though the higher, well-tolerated dose of 40 mg/kg should also be considered, particularly if resources allow for multiple doses in a given in vivo experiment.