WEE1-IN-7

This appears to be a slightly more selective Wee1 inhibitor (in biochemical assays) than the other one listed in the portal - the different chemotype suggests that perhaps using both in an orthogonal manner to investigate pharmacology may increase confidence in the validity of data obtained. Selectivity data in cells is not described but may be in part responsible for the observed activity - this is not uncommon for kinase inhibitors and does not preclude its use but appropriate controls and observations of pharmacology consistent with Wee1 mechanism of action can further increase confidence.

Wee1-IN-12h is currently one of the best available tool compounds for the WEE1 protein kinase. It is a potent, ATP-competitive inhibitor, exhibiting a Kd of 2.1 nM. It has been developed primarily for therapeutic applications, which reflects its selectivity and characterization. It shows good selectivity in a panel of 225 protein kinases at a 1 µM concentration, where it inhibited 4 additional off-targets above the threshold of 80% inhibition (GAK, MAP3K19, MAP3K3, and PLK1). Further characterization of these off-targets is missing, as well as a negative control compound. A strong point is the extensive characterization in mice, showing a very decent PK profile. In addition, Wee1-IN-12h shows very good efficacy in the Lovo CDX model (a xenograft mouse model using colorectal cancer cells). While this compound can be a useful tool for in cellulo and in vivo experiments, the potential user should be aware of possible off-target effects and consider further profiling (e.g., in cellulo target engagement for WEE1 and possible off-targets or wider kinome profiling).