Identification and Characterization of a Novel Integrin-Linked Kinase Inhibitor

Abstract

Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-Methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC50, 0.6 μM), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1 – 2.5 μM), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3β and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.

Signals from the surface modulate differentiation of human pluripotent stem cells through glycosaminoglycans and integrins

“…ILK is largely studied for its role in cancer (35) and epithelial-mesenchymal transition (44). Although whether ILK contains a functional kinase domain is debatable (45), there is evidence that its role as an oncogene stems from its ability to activate its downstream effector Akt, a signaling hub in both cancer and pluripotency.…”

“…We used a chemical biology approach to dissect the contribution of these pathways. Cells (H9) were cultured on Matrigel with differentiation medium supplemented with the FAK inhibitor PF-573,228 (34) or ILK inhibitor Cpd 22 (35). At greater than 1 μM PF-537,228 or 0.7 μM Cpd 22, we observed cell toxicity.…”

OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells

“…36 OSU-arg was acquired from the National Cancer Institute (Bethesda, MD). Stock solutions were prepared in dimethylsulfoxide.…”

“…21 Given that OSU-T315 has been shown to inhibit activation of AKT and ERK through targeting ILK in solid tumors, 36 components of key signaling pathways were evaluated following OSU-T315 treatment in Mec-1 and OSU-CLL cells ( Figure 3A and Table 2). Consistent with the previous report, this cellular profiling demonstrates notably diminished AKT and ERK phosphorylation on Table 3.…”

“…35 Recently, generation of the novel ILK inhibitor OSU-T315 was reported. 36 Given the justification that targeted therapy directed at ILK would be effective in CLL through suppressing AKT and/or ERK activation, we pursued preclinical in vitro and in vivo studies to determine the activity of OSU-T315 toward primary CLL cells. Concurrently, we demonstrate that this agent caused disruption of PI3K and MAPK signaling promoted by BCR or integrin engagement, besides specific inhibition of PI3K axis mediated by CD40 and TLR9.…”