ACK1 INHIBITOR, (R)-9b

ACK1 activation in cancers

(i) ACK1 integrates signals from various receptor tyrosine kinases, e.g. MERTK, AXL, EGFR, PDGFR, Insulin receptor, HER2. These kinases activate ACK1 in multiples cancers, including prostate, breast, lung, gastric, pancreatic, and many other cancers.

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

(iii) Autoactivating mutations and gene fusions

Identification of ACK1 inhibitor, (R)-9b

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 and PDX tumor growth.  

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

We have shown the crystal structure of (R)-9b bound to ACK1 kinase domain (Figure 2) Nature Communications, 2022.

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

Clinical trial of (R)-9b is expected to start in early 2025 (IND#167907. Dr. Nupam Mahajan nupam@wustl.edu 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).