OICR-9429

OICR-9429 is a small-molecule antagonist of the WDR5-MLL protein-protein interaction, a notoriously difficult class of molecular targets. There is solid evidence showing a direct in vitro interaction between OICR-9429 and its intended target, WDR5. This includes ITC and X-ray crystallography. This compound displays high affinity (Kd <100 nM) for WDR5. It has well-characterized, reversible binding kinetics. The authors also show (at least in vitro) that it does not significantly inhibit other many other HMTs, kinases or other pharmacologically relevant targets. There are convincing target-engagement data in cells via biotinylated pull-down proteomics and gene-expression profiling consistent with such engagement. It is effective in vitro versus p30-expressing cells. Note, there is <1-log difference is cytotoxicity of OICR-9429 to p30-expressing cells versus other cells, as reported in the original publication. Therefore, dosage of this probe should be carefully considered, perhaps even taking care to perform dose-response controls to rule out non-specific effects that may occur at higher compound concentrations. Users should take advantage of a close structural analog, OICR-0547, as a negative control compound. The authors present evidence showing the negative control compound does not disrupt the WDR5-MLL interaction in vitro. It has similar cytotoxoicity as OICR-9429 versus K562 cells. Users should also note that there is only ~1-log difference in cytotoxicity between the active compound and inactive analog.

Recommended concentration is based on the finding that the IC₅₀s for the disruption of WDR5-MLL and WDR5-RbBP5 complexes in co-IPs from HEK293 expressing Flag-WDR5 are 223 nM and 458 nM, respectively.