ULK-101

ULK-101 looks to be an appropriate tool for in vitro/in cellulo studies. Kinase selectivity data is included within the supplementary data. Further confidence in use as probe would come from availability of wider selectivity data (i.e. targets other than kinases) and ideally a negative chemical probe. The molecule may be suitable for in vivo use but no data are available. Additionally these data at present come from a single publication.

ULK-101 is a potentially valuable probe for studying ULK1 biology in cells, as it is potent against ULK-1 (8.3 nM) and quite selective against the kinome, with only 2 off-target kinases inhibited at similar potency levels (it was determined that the IC50 for DRAK1 is 14 nM and that of MNK2 to be 22 nM). Moreover, ULK-101 inhibits ULK2 at 30 nM, suggesting that at least at doses above 1 uM in cell tissue studies it has good coverage for this possibly redundant target as well. These features suggest that ULK-101 is a “best in class” probe against ULK1. It is slightly less potent than the structurally related analog ULK-100, but it is significantly more selective. There is no data disclosed against targets outside the kinase class, but the scaffold appears to have no features suggesting it should potently modify other protein classes (e.g ion channels, GPCRs). There is no disclosed in vivo efficacy or pharmacokinetic data, so use in the context of in vivo experiments should proceed with care until pharmacokinetic data or pharmacodynamic data is determined.