UNMCK90

The UNMCK90 putative probe compound is clearly a potent AKR1C3 inhibitor and shows very good selectivity over the closely related AKR1C1, 1C2 & 1C4 isozymes. However, I see no information regarding testing for off-target activity on any other target classes, as one might expect for a proposed probe. Also, no actual studies were done of this compound in cells and I can find no direct studies showing inhibition of AKR1C3 substrate to product conversion in cells. If the authors hypothesis for the MOA of these AKR1C3 inhibitors is true, i.e., that inhibition of AKR1C3-mediated metabolism of certain chemotherapeutics to their inactive hydroxyl derivatives and/or inhibition of AKR1C3 leads to a shift in relative levels of various prostaglandins in the cancer cell that disfavors differentiation and/or proliferation, then these may indeed be useful tools to pursue that line of investigation. However, I do not feel this particular compound 5r nor its putative methyl ester prodrug 4r, have been sufficiently well characterized to recommend them as approved probes.

UNMCK90 is a prodrug which can be converted to its free acid, compound 5r, in mouse plasma (UNMCK90 was reduced to below detectable in30 min) and in vivo (UNMCK90 was undetectable after 1 h post administration).Compound 5r is a potent AKR1C3 inhibitor showing 2 digit nano-molar level IC50with >1000 fold selectivity for AKR1C3 over closely related isoforms,AKR1C1, AKR1C2 and AKR1C4.As there is no cell-based assay in this work, the "recommended cellular concentration" is remained blank. For the design of the efficacy study, especially for preliminary dose determination, plasma protein binding needs to be measured at first and free drug level of compound in plasma needs to be calculated in thein vivo PK study. By comparing the free drug level to IC50, an efficacious dose can be determined. In the paper, it has not been described how 50 mg/kg and 25mg/kg were determined. Also the acrylate of the prodrug and acrylic acid of the free acid are both prone to glutathione conjugation, which is a common phase II metabolism pathway. In this work, the metabolic stability was only assessed in liver microsome, which majorly covers phase I metabolism pathway. These facts indicated potential off-target effects. If there is a broader target selectivity screening (i.e. kinase panel or Cerep) run for this compound, the efficacy data would be more convincing.