ACK1 integrates signals from various receptor tyrosine kinases, e.g. EGFR, PDGFR, Insulin receptor (IR), HER-2 and FGFR. These kinases activates ACk1 in prostate and breast cancers. Further, ACK1 is amplified in 40% of lung cancers. However, no ACK1 inhibitor has so far made it to clinical trial.

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

We generated a new class of small molecule ACK1 inhibitor (R)-9b, that has excellent drug-like properties. (R)-9b suppressed proliferation of various prostate, breast and lung xenograft tumor growth.  

Crystal structure of (R)-9b bound to ACK1

Recently with our collaborators, we have solved the crystal structure of (R)-9b bound to ACK1 kinase domain.

Pre-IND GLP-Tox studies with (R)-9b

(R)-9b has excellent ADME properties and exhibited no toxicity in rats even at high dosage. It also has oral efficacy.

Clinical Trial of ACK1 inhibitor, (R)-9b

Efforts are underway for the clinical trials of (R)-9b in prostate and breast cancer. Dr. Nupam Mahajan (nupam@wustl.edu) can be contacted by interested parties.

Compound (R)-9b (yellow) docked to ACK1 (pdb 4EWH), with ACK1 shown in ribbon representation with helices shown in red, β-strands shown as yellow arrows and loops shown in green.
Expanded stick model of (R)-9b (yellow) docked to the ATP binding site of ACK1, showing the amino acid residues of the kinase hinge in stick representation.