Three mechanisms of ACK1 activation

(i) ACK1 integrates signals from various receptor tyrosine kinases, e.g. MERTK, EGFR, PDGFR, Insulin receptor, HER2. These kinases activate ACK1 in multiples cancers, including prostate & breast.

(ii) ACK1/TNK2 gene is amplified in 40% of lung cancers, 30% of breast cancers and 10% of prostate cancers.

(iii) Autoactivating mutations

Identification of ACK1 inhibitor, (R)-9b

In spite of its significance, no ACK1 inhibitor has so far made it to clinical trial. We generated a new class of small molecule ACK1 inhibitor (R)-9b (Figure 1), 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 (Figure 2) Nature Communications, 2022.

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

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

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

Clinical trial of (R)-9b is expected to start in 2023. Dr. Nupam Mahajan can be contacted by interested parties.

Figure 1. Structure of (R)-9b in mesylate form
Figure 2. X-ray co-crystal structure of ACK1 kinase domain bound to (R)-9b. The compound (R)-9b binds to the ATP binding site underneath the phosphate binding P-loop (red), without interactions to helix αC (orange) or the activation loop (blue).