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 30% of lung cancers, 20% of Urothelial carcinoma (bladder cancer), 20% of Esophageal carcinoma and 17% of ovarian cancers.

(iii) A significant increase in ACK1 transcripts is also seen in prostate cancer, esophageal cancer and lung squamous cell carcinoma (Figure 3).

(iv) 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 that has excellent drug-like properties. (R)-9b suppressed proliferation of various prostate, breast and lung xenograft and PDX tumor growth.  

ACK1 inhibits syngeneic tumor growth by activating T cells

The B6 mice injected with (R)-9b exhibited a marked decrease in tumor growth (Figure 1). Harvested lymph nodes from the (R)-9b-treated mice revealed a significant increase in the number of CD137+/CD8+ cytotoxic T cells, effector CD44hiCD62Llow CD8+ T cells. Nature Communications, 2022.

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

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

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

Phase I Clinical trial (PHAROS) 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. (R)-9b suppresses syngeneic tumor growth by activating T cells

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).

Figure 3. Enhanced expression of ACK1 (encoded by TNK2 gene) in Prostate cancer, Esophageal cancer and Lung squamous cell carcinoma.