Effects of SLx-2119, a novel small molecule inhibitor of Rho-associated kinase ROCK (ROK), on growth of human tumor xenografts in nude mice

摘要: 668 A Ser/Thr kinase ROCK (Rho-associated coiled-coil forming protein kinase) is a downstream effector of small Ras-like GTPase Rho. The Rho-ROCK signaling pathway controls cell shape, adhesion, contractility, and motility invasion. Thus, testing inhibitors in animal models cancer was previously focused mostly on their anti-metastatic effects. goal the present study however, to determine whether novel class ROCK-selective will directly affect growth primary tumors human tumor xenograft-bearing mice. We have developed series that are potent selective vitro: they inhibit both isoforms with Ki’s for ROCK2 5 35 nM, ROCK1 25 120 nM; other kinases (insulin receptor, Aurora A, checkpoint CHK1, PKA, Abl, etc.) were 300- 1,500-fold higher. In cell-based assays, addition these culture medium resulted morphological changes characteristic inhibition signaling, i.e., disappearance actin stress fibers decrease number focal adhesions mouse Swiss 3T3 fibroblasts types. also blocked ROCK-dependent cellular responses, lysophosphatidic acid-induced neurite retraction N1E-115 neuroblastoma cells, as well serum-stimulated migration HT-1080 fibrosarcoma cells. latter assay, more than standard inhibitor Y-27632: IC50s between 15 uM, whereas IC50 Y-27632 50 uM. Next, we tested this has direct effect xenograft nude Oral administration mice bearing staged fibrosarcomas or PANC-1 pancreatic significant delay. For example, 10 days daily treatment 60 mg/kg p.o. SLx-2119 11-12 post-treatment delay model. efficacious cytotoxic positive (doxorubicin gemcitabine). dose-dependent accompanied by acceptable toxicity: did not show any behavior abnormalities, weight loss exceed 12% at highest dose tested. Taken together, our results suggest reported metastasis, may tumors.