A Novel ACK1/TNK2 Small Molecule Inhibitor, (R)-9bMS

Need for ACK1 inhibitor

Inhibition of one Receptor tyrosine kinase (RTKs) may not be sufficient for the most tumor regression. Since ACK1 is able to integrate signals from various RTKs, e.g. EGFR, PDGFR, Insulin receptor, HER-2, ACK1 inhibitors could effectively block signal from multiple RTKs and thus would have significant anti-proliferative effects in prostate, breast, ovarian, pancreatic and lung cancer patients. However, ACK1-specific inhibitor is currently not available for clinical trial.

 

Identification of the novel ACK1 inhibitor, (R)-9b

We generated compound libraries which was screened for ACK1 inhibition using a novel ELISA (Enzyme-Linked Immunosorbent Assay) that was developed in our lab. Subsequently, IC50 for those compounds that inhibited ACK1 activity by >90% were determined. The treatment of various cancer cells with resulted in almost complete loss of ACK1 activation. 

The most potent compound in the cell experiments, (R)-9b was subjected to extensive kinase profiling (n=369 kinases) to determine its selectivity. ACK1 was the kinase most potently inhibited (99.8 % inhibition). 

Structure of (R)-9b mesylate salt