Cycloartanes with Anticancer Activity Demonstrate Promising inhibition of the Mrckα and Mrckβ Kinases

Aim: The role of Kinases in cancer onset and progression has made kinases a target for the control of some cancers. Recent discoveries that kinases are most effectively inhibited by small molecules have also resulted in an increased search for small molecule kinase inhibitors. Cycloartanes are small molecules found in many medicinal plants including the Jamaican Ball Moss (Tillandsia recurvata). Recent studies on T. recurvata have demonstrated that it possesses anticancer activity. Cycloartane-3,24,25-triol, an analog of a cycloartane identified in Ball moss was also shown to have inhibitory activity against MRCKα kinase. This study was as such set up to determine the MRCKα/β kinase inhibition activity of other cycloartanes in Ball Moss and their analogs. MRCKα/β kinases has been identified as an important kinase implicated in cancer onset and progression and as such a potential drug target.
Methodology: Kinase inhibition activity of 6 cycloartanes was investigated using the ligand-kinase binding assay. The WST-1 reagent assay was also used to determine the antiproliferation activity of the cycloartanes against some prostate and breast cancer cell lines.
Results: Cycloart-23-ene-3,25-diol (1), Cycloartane-3,24,25-triol (2), Cycloart-25-ene-3,24-diol (3), 3,23-Dioxo-9,19-cyclolanost-24-en-26-oic acid (4), 24,25-Dihydroxycycloartan-3-one (5) inhibited the MRCKα kinase with Kd of 0.21 μM, 0.25µM, 0.36 µM, 3.0 µM and 2.1 µM respectively. Hydroxycycloart-23-en-3-one,25, (6) showed no inhibition against the MRCKα kinase. Compounds 1, 3, 4, 5 inhibited the MRCKβ kinase with Kd of 4.7 μM, 1.10 µM, 3.2 µM and 9.8 µM, respectively. Three of the six cycloartanes exhibited antiproliferation activity against two prostate and breast cancer cell lines each.
Conclusion: Cycloart-23-ene-3,25-diol (1) showed the most promising activity against the MRCKα/β kinase out of the 6 cycloartanes screened demonstrating an interesting structure activity relationship profile when compared with the other molecules. Cycloart-23-ene-3,25-diol (1) deserves further studies to determine itsin vivo activity as well.