New Inhibitors The Tyrosine Kinase Ack1/Tnk2 Active In Prostate, Breast And Pancreatic Cancer

ACK1, is a non-receptor tyrosine kinase that is aberrantly activated, over expressed or mutated in many cancer cell types. It interacts with several important ligand-activated receptor tyrosine kinases (RTKs), for example, EGFR, MerTK, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. ACK1 activation has been reported in various cancers including prostate, breast and pancreatic tumors. We have shown that the androgen receptor (AR) and AKT are two major downstream effectors of ACK1. ACK1 directly phosphorylates AKT at Tyr176 resulting in AKT membrane localization and activation. We have also found that in prostate cancer cells ACK1 phosphorylates AR at Tyr-267 in an androgen-independent manner. Tyr284-phosphorylated-ACK1, Tyr176-phosphorylated-AKT and Tyr267-phosphorylated-AR levels are positively correlated with the severity of disease progression, and inversely correlated with the survival of patients with prostate cancer. Similarly, ACK1 mediated AKT tyrosine phosphorylation was found to correlate positively with breast cancer progression. Further, we have shown that a 5,6-biaryl-furo[2,3-d]pyrimidine inhibitor of ACK1 (AIM-100) inhibits ACK1 activation and suppresses pTyr267-AR phosphorylation and AKT Tyr176-phosphorylation, inhibiting AR and AKT activity. These findings indicate that Ack1 is prognostic of progression of prostate, breast and pancreatic cancer and inhibitors of ACK1 activity have potential as novel cancer therapeutic agents. We will discuss the development of new potent ACK1 inhibitors by fragment-recombination and structure-based design by incorporating fragments of key ACK1 inhibitors. Focused chemical libraries were developed and structure activity relationships will be described. The work described has produced compounds capable of inhibiting ACK1 in vitro at low nanomolar concentrations. We have used an ELISA based assay that measures the ability of ACK1 to phosphorylate a peptide derived from AKT, as a primary screening assay. ACK1 inhibition of hits was confirmed in the 33P ATP “Hotspot” assay platform. Selected compounds from the library have been shown to inhibit ACK1 autophosphorylation and the phosphorylation of AR at Tyr267, a surrogate for ACK1 inhibition in vivo. Furthermore we will show that ACK1 is a promising drug target for cancer therapy. Citation Format: Harshani R. Lawrence, Yunting Luo, Daniel Zhang, Nathan Tindall, Sevil Ozcan, Miles Huseyin, Sakib Kazi, Sayantani Bandyopadhyay, Kiran Mahajan, Nupam P. Mahajan, Nicholas J. Lawrence. New inhibitors the tyrosine kinase ACK1/TNK2 active in prostate, breast and pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2511. doi:10.1158/1538-7445.AM2014-2511