Description
Filanesib, also known as ARRY-520, is a synthetic, small molecule targeting the kinesin spindle protein (KSP) with potential antineoplastic activity. KSP inhibitor ARRY-520 specifically inhibits KSP (kinesin-5 or Eg5), resulting in activation of the spindle assembly checkpoint, induction of cell cycle arrest during the mitotic phase, and consequently cell death in tumor cells that are actively dividing. Because KSP is not involved in postmitotic processes, such as neuronal transport, this agent does not cause the peripheral neuropathy that is often associated with tubulin-targeting agents.
in vitro
Inhibition of KSP by ARRY-520 blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells._x000D_
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Reference: Leukemia. 2009 Oct;23(10):1755-62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593228/
target
Filanesib TFA (ARRY-520 TFA) is a selective kinesin spindle protein (KSP) inhibitor, with an IC50 of 6 nM for human KSP.
