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  • br ACK inhibitors Since ACK activation


    ACK1 inhibitors Since ACK1 activation is correlated with poor prognosis in various cancers, strong efforts are being directed by multiple groups towards developing highly potent and specific small molecule inhibitors targeting the ACK1 kinase. At least eight small molecule kinase inhibitors have so far been reported in literature (Table 1). The effectiveness of these small molecule inhibitors in vitro and their ability to block cancer cell growth is discussed below.
    Future perspective: ACK1 allosteric inhibitors The ACK1 inhibitors that have so far been reported in literature are all ATP analogs; indeed, large majority of small molecule kinase inhibitors reported in literature target the ATP-binding site of kinases [61]. ATP competitive inhibitors (type I inhibitors) often do not discriminate effectively between ATP pitavastatin of multiple kinases [62]. This potentially limits their clinical use and increases the likelihood of off-target toxicity. Specificity is particularly important not only to interrogate the cellular biochemistry but also its effectiveness in suppressing tumor growth – ultimate utility as a personal therapeutic strategy. Approaches that seek non-competitive or purely allosteric inhibitors (type II–III inhibitors), which target kinase-specific regulatory sites, may offer better opportunities for selective inhibitor design [61], [63], [64], [65], [66]. An allosteric inhibitor of ACK1 would represent a novel type of ACK1 inhibitor and a preferred therapeutic agent. Because ACK1 is large multi-domain protein and inter-domain interactions are critical for its kinase activation, it is possible to achieve noncompetitive inhibition of ACK1 from a change in the shape of the active site when a small molecule or a peptide binds to an allosteric site located within the kinase domain or even neighboring SAM, SH3 or CRIB domains. Affinity Selection–Mass Spectrometry (AS–MS) has emerged to be a screening technology of choice for identification of potential allosteric inhibitors [67], [68], [69], [70], [71]. However, no ACK1-specific allosteric inhibitor has been identified so far.
    Conflict of interest
    Introduction Ack1, a member of tyrosine kinase family, was first identified as a non-GTP binding protein by Manser et al. when human hippocampal cDNA library was screened to find out the proteins which could act on the small G-protein Cdc42. Ack1 was found as the only specifically binding protein to Cdc42 [1]. The gene coding Ack1 is localized on chromosome 3q29 in human. It is deduced to be a protein consisting of 1091 amino acids with a molecular weight of 120 KD. Cytoplasmic distribution showed that this gene is able to catalyze the phosphorylation of the tyrosine residues in the substrate, as well as to activate the substrate enzymes, involved in several signaling pathways, and is associated with multiple biological activities (e.g. cellular proliferation/adhesion, cytoskeletal rearrangements etc.) [2], [3], [4]. Meanwhile, Ack1 also plays an important role in facilitating tumorigenesis, tumor invasion and metastasis [5], [6], [7], [8], [9]. Recent research suggested that Ack1 is becoming the target of tumor chemotherapy [10], [11], [12].
    Material and methods
    Discussion In our present study, the expressions of Ack1 in HCC tissues, peri-HCC tissues and distal-HCC tissues were assessed at both the mRNA and protein levels. The correlations between Ack1 expression and the pathology in the patients with HCC were also investigated. The results from RT-PCT and Western blotting confirmed that the mRNA and protein expression of Ack1 was significantly higher in HCC than in the peri- or distal-HCC tissues (Fig. 1, Fig. 2, <0.05). The above results indicated that Ack1 was highly expressed in the HCC tissues, and it was associated with the pathogenesis of HCC. Upregulation of Ack1 expression was also found in gastric cancer [9], [14], pancreatic cancer [15], prostate cancer [16], breast cancer [17] and esophageal squamous cell carcinomas [5]. Our finding in HCC confirmed the above study. Prieto-Echague et al. also found that the overexpression of wild type Ack1 promotes the transformed phenotype. Overexpression of WT Ack1 in cells showed high levels of migration and caused a loss of contact inhibition in cells growing attached to a surface and allowed the cells to survive in nonanchored conditions [7]. Other studies have demonstrated that gene amplification, a single somatic mutation in Ack1 can result in extended protein stability, enabling the oncoprotein to exert its oncogenic function in tumor progression [7], [18]. Ack1 activates AKT directly in pancreatic cancer and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival [12], [17]. In addition, Ack1 downregulated the anti-oncogene Wwox and enhanced the growth of prostate cancer cells. Ack1 and Wwox interaction led to the tyrosine phosphorylation and polyubiquitination and thus induced Wwox degradation [16]. It is interesting that frequent downregulation and loss of Wwox gene expression were observed in HCC [19], [20]. The molecular mechanism between Ack1 and Wwox in HCC tumorigenesis will be elucidated in our further studies.