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8054 is more AURKAspecific because of its ability to inhibit T288 phosphorylation, increasing Afatinib within the mitotic cells invivo. We recently reportedinduction of TAp73 at protein level together with variousproapoptotic genes, PUMA, NOXA and p21 by MLN8054 in diverse p53 deficient tumorcells. p53 deficient cells are resistant to chemotherapy. This observation whereby MLN8054induced TAp73 could prove to be valuable in targeting tumors lacking p53.MLN8237MLN8237is a secondgeneration AURKA inhibitor and has recently enteredphase III clinical trials. It inhibits AuroraA with an IC50 of 1nM in biochemicalassays and has 200fold selectivity for AURKA over AURKAB in cell assays. A broad screenof receptors and ion channels showed no significant crossreactivity. The compound blocksthe growth of numerous tumor cell lines with GI50 values as low as 16nM.
Growth inhibitionis connected with mitotic spindle abnormalities, accumulation of cells in mitosis, polyploidy,and apoptosis. It can be orally accessible and Afatinib rapidly absorbed. At successful doses a transientinhibition of histone H3 phosphorylation is observedfollowed by marked elevation of histone H3 phosphorylation. Maximum in vivo efficacy, in numerous xenografts, hasbeen achieved with oral doses of 20mgkg offered twice per day for 21 consecutive days, althoughother regimens are also successful. MLN8237 in combination Rituximab was discovered to reducetumor burden in an additive andor synergistic mechanism in numerous Diffuse Substantial BcellLymphoma tumor models.PHA680632PHA680632is a potent inhibitor of Aurora kinase family members Everolimus members with IC50s of27, 135 and 120nmolL for AuroraA,B andC, respectively; and shows the strongest crossreactivity for FGFR1.
PHA608632 is reported to have a potent antiproliferative VEGF activityin a wide range of cancer cell lines. PHA680632 inhibits AURKA autophosphorylationat T288 and AURKB mediated phosphorylation of histone H3phenotypes, which areconsistent using the inhibition of AURKA and AURKB. Inhibition of AURKA by PHA680632in p53HCT116 cells followed by radiation therapy enhanced response in apoptosis.This additive effect of PHA680632 and IR radiation delayed tumor growth in xenograftsmodel, inhibiting colony formation and induced polyploidy. PHA680632 brought aboutadditive interaction with radiation in terms of induced cell death in p53 nonfunctional cells.Such additivity could possibly be valuable in chemoradiotherapeutic combinations.
PHA680632 andradiotherapy might be employed concomitantly or in close temporal proximity, potentially withoutacute or late healthful tissue complications.PHA739358PHA739358is more potent than its predecessor PHA680632 and inhibits all threeAurora Kinases A, B and C with IC50s of 13, 79 and 61nmolL, respectively. It has a highcrossreactivity Everolimus for other kinases mutated or overexpressed in cancers like Ret, TrkA andAbl. It inhibits phosphorylation of AURKA on T288 and reduces histone H3 phosphorylationindicating AURKB inhibition. Lately, PHA739358 has been reported to show strongantiproliferative action in chronic myeloid leukemiacells and is successful againstImatinibresistant BcrAbl mutations such as T3151that could result in its use as atherapeutic target for myeloid leukemia patients, particularly those that developed resistance toGleevec.
PHA739358 is presently being evaluated in a phase II clinical trial in CML, includingpatients with T315I mutation. Afatinib PHA739358 has significant antitumor activity in transgenictumor models having a favorable preclinical safety profile; principal target organs ofPHA739358 would be the hemolymphopoietic method, gastrointestinal tract, male reproductiveorgans and kidneys. Renal effects, nevertheless, are only noticed at high drug exposure.HesperidinHesperidinis specific for AURKB as indicated by the reduction ofhistone H3 phosphorylation and exhibiting the similar phenotype to AURKB knockdown. It has cross reactivity for six other kinasesand proved beneficial to understand the biology of AURKB function.
Hesperidinimpairs the Everolimus localization of checkpoint proteins including BUB1 and BUBR1 to kinetochore, andinduces cytokinesis and polyploidy. Hesperidin was instrumental in understanding the role ofAURKB in syntelic orientation of chromosomes and spindle assemble checkpoint.ZM447439ZM447439inhibits AuroraA andB with IC50 values of 110 and 130nMresulting within the reduction of phosphorylation of histone H3. ZM447439 therapy causesdefects in chromosome alignment, segregation, and cytokinesis; most likely by interfering withthe spindle integrity checkpoint. Cells treated with ZM447439 pass by means of Sphase, failto divide and after that enter a second Sphase because of failure in chromosome alignment andsegregation. In p53 deficient cells ZM447439 enhanced endoreduplication, in comparison with p53proficient cells, suggesting that p53independent mechanisms might also have an effect on ZM447439induced tetraploidization. The effects mediated by ZM447439arecharacteristic to AURKB inhibition as an alternative to AURKA. ZM447439 therapy onxenopus eggs exhibited no detectable effects on frequenc