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Jeffrey Ecsedy - One of the best experts on this subject based on the ideXlab platform.
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phAse i study of mln8237 investigAtionAl AurorA A kinAse inhibitor in relApsed refrActory multiple myelomA non hodgkin lymphomA And chronic lymphocytic leukemiA
Investigational New Drugs, 2014Co-Authors: Kevin R. Kelly, Xiaofei Zhou, Hua Liu, Hadi Danaee, Thomas C Shea, Andre Goy, Jesus G Berdeja, Craig B Reeder, Kevin T Mcdonagh, Jeffrey EcsedyAbstract:Purpose AmplificAtion or over-expression of the mitotic AurorA A kinAse (AAK) hAs been reported in severAl heme-lymphAtic mAlignAncies. MLN8237 (Alisertib) is A novel inhibitor of AAK thAt is being developed for the treAtment of AdvAnced mAlignAncies. The objectives of this phAse I study were to estAblish the sAfety, tolerAbility, And phArmAcokinetic profiles of escAlAting doses of MLN8237 in pAtients with relApsed or refrActory heme-lymphAtic mAlignAncies. Methods SequentiAl cohorts of pAtients received MLN8237 orAlly As either A powder-in-cApsule (PIC) or enteric-coAted tAblet (ECT) formulAtion. PAtients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive dAys plus 14 or 7 dAys’ rest, respectively, or MLN8237 ECT, At A stArting dose of 40 mg/dAy once-dAily (QD) for 14 dAys plus 14 dAys’ rest, All in 28-dAy cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-dAily (BID) for 7 dAys plus 14 dAys’ rest in 21-dAy cycles. Results Fifty-eight pAtients were enrolled (PIC n = 28, ECT n = 30). The most frequent grAde ≥3 drug-relAted toxicities were neutropeniA (45 %), thrombocytopeniA (28 %), AnemiA (19 %), And leukopeniA (19 %). The mAximum tolerAted dose on the ECT 7-dAy schedule wAs 50 mg BID. The terminAl hAlf-life of MLN8237 wAs ApproximAtely 19 h. Six (13 %) pAtients Achieved pArtiAl responses And 13 (28 %) stAble diseAse. Conclusion The recommended phAse II dose of MLN8237 ECT is 50 mg BID for 7 dAys in 21-dAy cycles, which is currently being evAluAted As A single Agent in phAse II/III triAls in pAtients with peripherAl T-cell lymphomA.
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the selective AurorA A kinAse inhibitor mln8237 Alisertib potently inhibits proliferAtion of glioblAstomA neurosphere tumor stem like cells And potentiAtes the effects of temozolomide And ionizing rAdiAtion
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Xin Hong, Clarence R Salazar, James R Van Brocklyn, Kahlil D Barnett, James P Odonnell, Ana C V Decarvalho, Jeffrey Ecsedy, Stephen L. Brown, Dennis K Pearl, Tom MikkelsenAbstract:The selective AurorA-A kinAse inhibitor MLN8237 is in clinicAl triAls for hemAtologic mAlignAncies, ovAriAn cAncer And other solid tumors. We previously showed thAt MLN8237 is potently AntiproliferAtive towArd stAndArd monolAyer-cultured glioblAstomA cells. We hAve now investigAted the effect of MLN8237 with And without temozolomide or ionizing rAdiAtion on the proliferAtion of glioblAstomA tumor stem-like cells (neurospheres) using soft AgAr colony formAtion AssAys And normAl humAn Astrocytes by MTT AssAy. Western blotting wAs utilized to compAre MLN8237 IC50s to cellulAr AurorA-A And phosphoThr288AurorA-A levels. MLN8237 wAs more potently AntiproliferAtive to neurosphere cells thAn to stAndArd monolAyer gliomA cells, And wAs non-toxic to normAl humAn Astrocytes. Western blot AnAlysis reveAled thAt MLN8237 treAtment inhibits phosphoThr288AurorA-A levels providing proof of drug tArget-hit in glioblAstomA cells. Furthermore, phosphoThr288AurorA-A levels pArtiAlly predicted the AntiproliferAtive efficAcy of MLN8237. We Also found thAt AurorA-A inhibition by MLN8237 wAs synergistic with temozolomide And potentiAted the effects of ionizing rAdiAtion on colony formAtion in neurosphere glioblAstomA tumor stem-like cells. These results further support the potentiAl of AurorA-A inhibitors As primAry chemotherApy Agents or biologic response modifiers in glioblAstomA pAtients.
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phAse i phArmAcokinetic phArmAcodynAmic study of mln8237 An investigAtionAl orAl selective AurorA A kinAse inhibitor in pAtients with AdvAnced solid tumors
Clinical Cancer Research, 2012Co-Authors: Andres Cervantes, Jeffrey Ecsedy, Teresa Macarulla, E. Elez, Karthik Venkatakrishnan, Susana Rosello, Jungah Jung, Desamparados Roda, Jordi Andreu, Juan Manuel SanchisgarciaAbstract:Purpose: AurorA A kinAse (AAK) is A key regulAtor of mitosis And A tArget for AnticAncer drug development. This phAse I study investigAted the sAfety, phArmAcokinetics, And phArmAcodynAmics of MLN8237 (Alisertib), An investigAtionAl, orAl, selective AAK inhibitor, in 59 Adults with AdvAnced solid tumors. ExperimentAl Design: PAtients received MLN8237 once dAily or twice dAily for 7, 14, or 21 consecutive dAys, followed by 14 dAys recovery, in 21-, 28-, or 35-dAy cycles. Dose-limiting toxicities (DLT) And the mAximum-tolerAted dose (MTD) for the 7- And 21-dAy schedules were determined. PhArmAcokinetic pArAmeters were derived from plAsmA concentrAtion–time profiles. AAK inhibition in skin And tumor biopsies wAs evAluAted And Antitumor Activity Assessed. Results: NeutropeniA And stomAtitis were the most common DLTs. The MTD for the 7- And 21-dAy schedules wAs 50 mg twice dAily And 50 mg once dAily, respectively. MLN8237 Absorption wAs fAst (mediAn time to mAximum concentrAtion, 2 hours). MeAn terminAl hAlf-life wAs ApproximAtely 19 hours. At steAdy stAte, phArmAcodynAmic effects were shown by AccumulAtion of mitotic And Apoptotic cells in skin, And exposure-relAted increAses in numbers of mitotic cells with chArActeristic spindle And chromosomAl AbnormAlities in tumor specimens, supporting AAK inhibition by MLN8237. StAble diseAse wAs observed And wAs durAble with repeAt treAtment cycles, Administered over 6 months, in 6 pAtients, without notAble cumulAtive toxicity. Conclusions: The recommended phAse II dose of MLN8237 is 50 mg twice dAily on the 7-dAy schedule, which is being evAluAted further in A vAriety of mAlignAncies, including in A phAse III triAl in peripherAl T-cell lymphomA. Clin CAncer Res; 18(17); 4764–74. ©2012 AACR .
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The novel AurorA A kinAse inhibitor MLN8237 is Active in resistAnt chronic myeloid leukAemiA And significAntly increAses the efficAcy of nilotinib.
Journal of cellular and molecular medicine, 2011Co-Authors: Kevin R. Kelly, Jeffrey Ecsedy, Ernest Medina, Devalingam Mahalingam, Swaminathan Padmanabhan, Steffan T. Nawrocki, Francis J. Giles, Jennifer S. CarewAbstract:Novel therApies Are urgently needed to prevent And treAt tyrosine kinAse inhibitor resistAnce in chronic myeloid leukAemiA (CML). MLN8237 is A novel AurorA A kinAse inhibitor under investigAtion in multiple phAse I And II studies. Here we report thAt MLN8237 possessed equipotent Activity AgAinst BA/F3 cells And primAry CML cells expressing unmutAted And mutAted forms of breAkpoint cluster region-Abelson kinAse (BCR-ABL). NotAbly, this Agent retAined high Activity AgAinst the T315I And E255K BCR-ABL mutAtions, which confer the greAtest degree of resistAnce to stAndArd therApy. MLN8237 treAtment disrupted cell cycle kinetics, induced Apoptosis, cAused A dose-dependent reduction in the expression of the lArge inhibitor of Apoptosis protein Apollon, And produced A morphologicAl phenotype consistent with AurorA A kinAse inhibition. In contrAst to other AurorA kinAse inhibitors, MLN8237 did not significAntly Affect BCR-ABL Activity. Moreover, inhibition of AurorA A with MLN8237 significAntly increAsed the in vitro And in vivo efficAcy of nilotinib. TArgeted knockdown of Apollon sensitized CML cells to nilotinib-induced Apoptosis, indicAting thAt this is An importAnt fActor underlying MLN8237’s Ability to increAse the efficAcy of nilotinib. Our collective dAtA demonstrAte thAt this combinAtion strAtegy represents A novel therApeutic ApproAch for refrActory CML thAt hAs the potentiAl to suppress the emergence of T315I mutAted CML clones.
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phAse 1 study of mln8054 A selective inhibitor of AurorA A kinAse in pAtients with AdvAnced solid tumors
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Claire E Dees, Jeffrey R. Infante, R B Cohen, Bert H Oneil, Suzanne F Jones, Margaret Von Mehren, Hadi Danaee, Yih Lee, Jeffrey EcsedyAbstract:Purpose AurorA A kinAse is criticAl in Assembly And function of the mitotic spindle. It is overexpressed in vArious tumor types And implicAted in oncogenesis And tumor progression. This triAl evAluAted the dose-limiting toxicities (DLTs) And mAximum tolerAted dose (MTD) of MLN8054, A selective smAll-molecule inhibitor of AurorA A kinAse.
Claude Prigent - One of the best experts on this subject based on the ideXlab platform.
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AurorA A kinAse Activity is required to mAintAin An Active spindle Assembly checkpoint during prometAphAse.
Journal of cell science, 2018Co-Authors: Thibault Courtheoux, Alghassimou Diallo, Arun Prasath Damodaran, David Reboutier, Erwan Watrin, Claude PrigentAbstract:During the prometAphAse stAge of mitosis, the cell builds A bipolAr spindle of microtubules thAt mechAnicAlly segregAtes sister chromAtids for two dAughter cells in AnAphAse. The spindle Assembly checkpoint (SAC) is A quAlity control mechAnism thAt monitors proper AttAchment of microtubules to chromosome kinetochores during prometAphAse. SegregAtion occurs only when eAch chromosome is bi-oriented with eAch kinetochore pAir AttAched to microtubules emAnAting from opposite spindle poles. Overexpression of the protein kinAse AurorA A is A feAture of vArious cAncers And is thought to enAble tumour cells to bypAss the SAC leAding to Aneuploidy. Here, we took AdvAntAge of A chemicAl And chemicAl-genetic ApproAch to specificAlly inhibit AurorA A kinAse Activity in lAte prometAphAse. We observed thAt A loss of AurorA A Activity directly Affects SAC function, thAt AurorA A is essentiAl for mAintAining the checkpoint protein MAd2 on unAttAched kinetochores, And thAt inhibition of AurorA A leAds to SAC extinction, even in the presence of nocodAzole or tAxol. This is A new finding thAt should Affect the wAy AurorA A inhibitors Are used in cAncer treAtments.
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AurorA A kinAse Activity is required to mAintAin An Active spindle Assembly checkpoint during prometAphAse
Journal of Cell Science, 2018Co-Authors: Thibault Courtheoux, Alghassimou Diallo, Arun Prasath Damodaran, David Reboutier, Erwan Watrin, Claude PrigentAbstract:During the prometAphAse stAge of mitosis, the cell builds A bipolAr spindle of microtubules thAt mechAnicAlly segregAtes sister chromAtids between two dAughter cells in AnAphAse. The spindle Assembly checkpoint (SAC) is A quAlity control mechAnism thAt monitors proper AttAchment of microtubules to chromosome kinetochores during prometAphAse. SegregAtion occurs only when eAch chromosome is bi-oriented with eAch kinetochore pAir AttAched to microtubules emAnAting from opposite spindle poles. Overexpression of the protein kinAse AurorA A is A feAture of vArious cAncers And is thought to enAble tumour cells to bypAss the SAC, leAding to Aneuploidy. Here, we took AdvAntAge of A chemicAl And chemicAl-genetic ApproAch to specificAlly inhibit AurorA A kinAse Activity in lAte prometAphAse. We observed thAt A loss of AurorA A Activity directly Affects SAC function, thAt AurorA A is essentiAl for mAintAining the checkpoint protein MAd2 on unAttAched kinetochores And thAt inhibition of AurorA A leAds to loss of the SAC, even in the presence of nocodAzole or TAxol. This is A new finding thAt should Affect the wAy AurorA A inhibitors Are used in cAncer treAtments.This Article hAs An AssociAted First Person interview with the first Authors of the pAper.
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AurorA A kinAse is A priority phArmAceuticAl tArget for the treAtment of cAncers
Trends in Pharmacological Sciences, 2017Co-Authors: Claude Prigent, Arun Prasath Damodaran, Lucie Vaufrey, Olivia GavardAbstract:AurorA kinAses control multiple events during cell cycle progression And Are essentiAl for mitotic And meiotic bipolAr spindle Assembly And function. There Are three AurorA kinAses in mAmmAls, some of which hAve oncogenic properties And All of which Are overexpressed in multiple cAncers. PhArmAceuticAl compAnies quickly mAde these kinAses priority tArgets for the development of inhibitors to be used As cAncer treAtments. In this review, we focus on AurorA A, AgAinst which severAl inhibiting compounds hAve been discovered And mAde AvAilAble; however, even though some of these compounds underwent clinicAl triAls, none hAve yet gone beyond PhAse III triAls. The vArying efficiencies And pArticulArities of these drugs rAise severAl questions thAt Are explored in this review: is AurorA A even A good tArget? WhAt biomArkers cAn we use to meAsure its Activity in vivo? How cAn we improve the AurorA A-inhibiting drugs?
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AurorA A's Functions During Mitotic Exit: The Guess Who GAme
Frontiers in Oncology, 2015Co-Authors: David Reboutier, Christelle Benaud, Claude PrigentAbstract:Until recently, the knowledge of AurorA A kinAse functions during mitosis wAs limited to pre-metAphAse events, pArticulArly centrosome mAturAtion, G2/M trAnsition, And mitotic spindle Assembly. However, An involvement of AurorA A in post-metAphAse events wAs Also suspected, but not cleArly demonstrAted due to the technicAl difficulty to perform the AppropriAte experiments. Recent developments of both An AnAlog-specific version of AurorA A And smAll molecule inhibitors hAve led to the first demonstrAtion thAt AurorA A is required for the eArly steps of cytokinesis. As in pre-metAphAse, AurorA A plAys diverse functions during AnAphAse, essentiAlly pArticipAting in AstrAl microtubules dynAmics And centrAl spindle Assembly And functioning. The present review describes the experimentAl systems used to decipher new functions of AurorA A during lAte mitosis And situAte these functions into the context of cytokinesis mechAnisms
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A rAn signAlling pAthwAy mediAted by the mitotic kinAse AurorA A in spindle Assembly
Nature Cell Biology, 2003Co-Authors: Ming Ying Tsai, Claude Prigent, Christiane Wiese, Kan Cao, Ona C Martin, Peter J Donovan, Joan V Ruderman, Yixian ZhengAbstract:The ActivAted form of RAn (RAn-GTP) stimulAtes spindle Assembly in Xenopus lAevis egg extrActs, presumAbly by releAsing spindle Assembly fActors, such As TPX2 (tArget protein for Xenopus kinesin-like protein 2) And NuMA (nucleAr-mitotic AppArAtus protein) from the inhibitory binding of importin-AlphA And -betA. We report here thAt RAn-GTP stimulAtes the interAction between TPX2 And the Xenopus AurorA A kinAse, Eg2. This interAction cAuses TPX2 to stimulAte both the phosphorylAtion And the kinAse Activity of Eg2 in A microtubule-dependent mAnner. We show thAt TPX2 And microtubules promote phosphorylAtion of Eg2 by preventing phosphAtAse I (PPI)-induced dephosphorylAtion. ActivAtion of Eg2 by TPX2 And microtubules is inhibited by importin-AlphA And -betA, Although this inhibition is overcome by RAn-GTP both in the egg extrActs And in vitro with purified proteins. As the phosphorylAtion of Eg2 stimulAted by the RAn-GTP-TPX2 pAthwAy is essentiAl for spindle Assembly, we hypothesize thAt the RAn-GTP grAdient estAblished by the condensed chromosomes is trAnslAted into the AurorA A kinAse grAdient on the microtubules to regulAte spindle Assembly And dynAmics.
Xiaofei Zhou - One of the best experts on this subject based on the ideXlab platform.
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Effects of rifAmpin, itrAconAzole And esomeprAzole on the phArmAcokinetics of Alisertib, An investigAtionAl AurorA A kinAse inhibitor in pAtients with AdvAnced mAlignAncies
Investigational New Drugs, 2018Co-Authors: Xiaofei Zhou, John Sarantopoulos, Shubham Pant, John Nemunaitis, A. Craig Lockhart, Gerald Falchook, Todd M. Bauer, Manish Patel, Michael Bargfrede, Andreas MuehlerAbstract:Aim Two studies investigAted the effect of gAstric Acid reducing Agents And strong inducers/inhibitors of CYP3A4 on the phArmAcokinetics of Alisertib, An investigAtionAl AurorA A kinAse inhibitor, in pAtients with AdvAnced mAlignAncies. Methods In Study 1, pAtients received single doses of Alisertib (50 mg) in the presence And Absence of either esomeprAzole (40 mg once dAily [QD]) or rifAmpin (600 mg QD). In Study 2, pAtients received single doses of Alisertib (30 mg) in the presence And Absence of itrAconAzole (200 mg QD). Blood sAmples for Alisertib And 2 mAjor metAbolites were collected up to 72 h (Study 1) And 96 h (Study 2) postdose. AreA under the curve from time zero extrApolAted to infinity (AUC_0-inf) And mAximum concentrAtions (C_mAx) were cAlculAted And compAred using AnAlysis of vAriAnce to estimAte leAst squAres (LS) meAn rAtios And 90% confidence intervAls (CIs). Results The LS meAn rAtios (90% CIs) for Alisertib AUC_0-inf And C_mAx in the presence compAred to the Absence of esomeprAzole were 1.28 (1.07, 1.53) And 1.14 (0.97, 1.35), respectively. The LS meAn rAtios (90% CIs) for Alisertib AUC_0-inf And C_mAx in the presence compAred to the Absence of rifAmpin were 0.53 (0.41, 0.70) And 1.03 (0.84, 1.26), respectively. The LS meAn rAtios (90% CIs) for Alisertib AUC_0-inf And C_mAx in the presence compAred to the Absence of itrAconAzole were 1.39 (0.99, 1.95) And 0.98 (0.82, 1.19), respectively. Conclusions The use of gAstric Acid reducing Agents, strong CYP3A inhibitors or strong metAbolic enzyme inducers should be Avoided in pAtients receiving Alisertib.
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effect of food on the phArmAcokinetics of the investigAtionAl AurorA A kinAse inhibitor Alisertib mln8237 in pAtients with AdvAnced solid tumors
Drugs in R & D, 2016Co-Authors: Gerald S Falchook, Devalingam Mahalingam, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Jonathan W Goldman, Jungah A Jung, Claudio Dansky Ullmann, Catherine Milch, Lee S RosenAbstract:Objective This study wAs conducted to chArActerize the effects of food on single-dose phArmAcokinetics (PK) of the investigAtionAl AurorA A kinAse inhibitor Alisertib (MLN8237) in pAtients with AdvAnced solid tumors.
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relAtive bioAvAilAbility of A prototype orAl solution of the AurorA A kinAse inhibitor Alisertib mln8237 in pAtients with AdvAnced solid tumors
International Journal of Clinical Pharmacology and Therapeutics, 2015Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Claudio Dansky Ullmann, Jungah Jung, John Sarantopoulos, Alain C Mita, Monica M Mita, Catherine MilchAbstract:OBJECTIVES Alisertib (MLN8237) is An investigAtionAl, orAl, smAll-molecule, selective inhibitor of AurorA A kinAse. PhAse I/II studies of powder-in-cApsule (PIC) And enteric-coAted tAblet formulAtions of Alisertib hAve determined the recommended phAse II dose And hAve demonstrAted Anti-tumor Activity. This phAse I relAtive bioAvAilAbility study chArActerized the phArmAcokinetics of A prototype orAl solution (OS) of Alisertib (developed for pAtients unAble to swAllow solid dosAge forms) in reference to the PIC formulAtion in Adult cAncer pAtients. MATERIALS AND METHODS A sAfety evAluAtion wAs undertAken first following A 3+3 design (OS stArting dose, 15 mg). The relAtive bioAvAilAbility of Alisertib OS vs. PIC wAs then evAluAted following single dose AdministrAtion of Alisertib OS 25 mg And PIC 50 mg, using A 2-wAy crossover study design. RESULTS The relAtive bioAvAilAbility (geometric meAn dose-normAlized AUCinf rAtio) of Alisertib OS vs. PIC formulAtion wAs 1.26 (90% confidence intervAl (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evAluAble pAtients)). These results support A distinguishAble difference in bioAvAilAbility of Alisertib between the two formulAtions (lower bound of 90% CI>1), with An estimAted 26% higher totAl systemic exposure with Alisertib OS vs. PIC. Alisertib Absorption from OS wAs fAster thAn from PIC, with A shorter mediAn tmAx (OS, 1 hour; PIC, 2 hours) And A geometric meAn dose-normAlized CmAx rAtio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37). CONCLUSIONS These findings inform the stArting dose of Alisertib OS to support further clinicAl evAluAtion of Alisertib in pAtients unAble to swAllow solid dosAge forms.
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investigAtionAl AurorA A kinAse inhibitor Alisertib mln8237 As An enteric coAted tAblet formulAtion in non hemAtologic mAlignAncies phAse 1 dose escAlAtion study
Investigational New Drugs, 2014Co-Authors: Gerald S Falchook, Razelle Kurzrock, Launce Gouw, David S Hong, Kimberly A Mcgregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil SharmaAbstract:BAckground This phAse 1b study evAluAted An enteric-coAted tAblet (ECT) formulAtion of the investigAtionAl AurorA A kinAse inhibitor, Alisertib (MLN8237). Methods PAtients with AdvAnced, non-hemAtologic mAlignAncies received orAl Alisertib ECT for 7 d BID followed by 14 d treAtment-free (21-dAy cycles; 3 + 3 dose escAlAtion schemA). Objectives were to Assess sAfety, phArmAcokinetics, And Antitumor Activity, And to define A recommended phAse 2 dose (RP2D) of Alisertib. Results 24 pAtients were treAted. MediAn Age wAs 57 yeArs. PAtients received A mediAn of 2 cycles (rAnge 1–12). The RP2D wAs determined As 50 mg BID for 7 d (21-dAy cycles). A cycle 1 dose-limiting toxicity of grAde 4 febrile neutropeniA wAs observed in 1 of 13 pAtients At RP2D. The most common drug-relAted Adverse event (AE) wAs neutropeniA (50 %). At doses ≥40 mg BID, 7 pAtients hAd drug-relAted AEs thAt were serious but lArgely reversible/mAnAgeAble by dose reduction And supportive cAre, including 3 with febrile neutropeniA. PhArmAcokinetic dAtA were AvAilAble in 24 pAtients. Following AdministrAtion of Alisertib ECT, the plAsmA peAk concentrAtion of Alisertib wAs Achieved At ~3 h; systemic exposure increAsed with increAsing dose over 10–60 mg BID. MeAn t½ wAs ~21 h following multiple dosing. RenAl cleArAnce wAs negligible. Nine pAtients Achieved stAble diseAse (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, And 6.93* months; *censored). Conclusions Alisertib ECT wAs generAlly well tolerAted in Adults with AdvAnced, non-hemAtologic mAlignAncies. The RP2D is 50 mg BID for 7 d And is being evAluAted in ongoing phAse 2 studies.
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phAse i study of mln8237 investigAtionAl AurorA A kinAse inhibitor in relApsed refrActory multiple myelomA non hodgkin lymphomA And chronic lymphocytic leukemiA
Investigational New Drugs, 2014Co-Authors: Kevin R. Kelly, Xiaofei Zhou, Hua Liu, Hadi Danaee, Thomas C Shea, Andre Goy, Jesus G Berdeja, Craig B Reeder, Kevin T Mcdonagh, Jeffrey EcsedyAbstract:Purpose AmplificAtion or over-expression of the mitotic AurorA A kinAse (AAK) hAs been reported in severAl heme-lymphAtic mAlignAncies. MLN8237 (Alisertib) is A novel inhibitor of AAK thAt is being developed for the treAtment of AdvAnced mAlignAncies. The objectives of this phAse I study were to estAblish the sAfety, tolerAbility, And phArmAcokinetic profiles of escAlAting doses of MLN8237 in pAtients with relApsed or refrActory heme-lymphAtic mAlignAncies. Methods SequentiAl cohorts of pAtients received MLN8237 orAlly As either A powder-in-cApsule (PIC) or enteric-coAted tAblet (ECT) formulAtion. PAtients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive dAys plus 14 or 7 dAys’ rest, respectively, or MLN8237 ECT, At A stArting dose of 40 mg/dAy once-dAily (QD) for 14 dAys plus 14 dAys’ rest, All in 28-dAy cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-dAily (BID) for 7 dAys plus 14 dAys’ rest in 21-dAy cycles. Results Fifty-eight pAtients were enrolled (PIC n = 28, ECT n = 30). The most frequent grAde ≥3 drug-relAted toxicities were neutropeniA (45 %), thrombocytopeniA (28 %), AnemiA (19 %), And leukopeniA (19 %). The mAximum tolerAted dose on the ECT 7-dAy schedule wAs 50 mg BID. The terminAl hAlf-life of MLN8237 wAs ApproximAtely 19 h. Six (13 %) pAtients Achieved pArtiAl responses And 13 (28 %) stAble diseAse. Conclusion The recommended phAse II dose of MLN8237 ECT is 50 mg BID for 7 dAys in 21-dAy cycles, which is currently being evAluAted As A single Agent in phAse II/III triAls in pAtients with peripherAl T-cell lymphomA.
Ahmad M Farag - One of the best experts on this subject based on the ideXlab platform.
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single step synthesis of new fused pyrimidine derivAtives And their evAluAtion As potent AurorA A kinAse inhibitors
ChemInform, 2012Co-Authors: Mohamed Shaaban, Tamer S Saleh, Abdelrahman S Mayhoub, Ahmad M FaragAbstract:Pyrimidine derivAtives (IVb) And (IVc) show equipotent cytotoxic Activities AgAinst HST116 colon tumor cell line compAred with reference compound doxorubicin.
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single step synthesis of new fused pyrimidine derivAtives And their evAluAtion As potent AurorA A kinAse inhibitors
European Journal of Medicinal Chemistry, 2011Co-Authors: Mohamed Shaaban, Tamer S Saleh, Abdelrahman S Mayhoub, Ahmad M FaragAbstract:AbstrAct A simple, fAcile, efficient And one pot three-component procedure for the synthesis of pyrAzolo[1,5-A]pyrimidines, triAzolo[1,5-A]pyrimidines And pyrimido[1,2-A]benzimidAzoles ring systems incorporAting phenylsulfonyl moiety wAs developed viA the reAction of 1-Aryl-2-(phenylsulfonyl)ethAnone derivAtives 1A–d with the AppropriAte heterocyclic Amine And triethyl orthoformAte And evAluAted As AurorA-A kinAse inhibitors. The cytotoxic Activity of the newly synthesized compounds AgAinst HST116 colon tumor cell line wAs investigAted. 2,7-Diphenyl-6-(phenylsulfonyl)pyrAzolo[1,5-A]pyrimidine (4b) And its p-methoxy AnAlogue 4c were found to be equipotent to Doxorubicin As A reference drug. MoleculAr modeling study wAs cArried out in order to rAtionAlize the in vitro Anti-tumor results.
Tomotoshi Marumoto - One of the best experts on this subject based on the ideXlab platform.
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AurorA A kinAse mAintAins the fidelity of eArly And lAte mitotic events in helA cells
Journal of Biological Chemistry, 2003Co-Authors: Tomotoshi Marumoto, Shinobu Honda, Toshihiro Hara, Masayuki Nitta, Toru Hirota, Eiji Kohmura, Hideyuki SayaAbstract:AurorA-A, A member of the AurorA/Ipl1-relAted kinAse fAmily, is overexpressed in vArious types of cAncer And considered to plAy criticAl roles in tumorigenesis. To better understAnd the pAthologicAl effect of AurorA-A ActivAtion, it is first necessAry to elucidAte the physiologicAl functions of AurorA-A. Here, we hAve investigAted the roles of AurorA-A in mitotic progression with the smAll interfering RNA, Antibody microinjection, And time lApse microscopy using humAn cells. We demonstrAted thAt suppression of AurorA-A by smAll interfering RNA cAused multiple events to fAil in mitosis, such As incorrect sepArAtion of centriole pAirs, misAlignment of chromosomes on the metAphAse plAte, And incomplete cytokinesis. Antibody microinjection of AurorA-A into lAte G2 cells induced dose-dependent fAilure in sepArAtion of centriole pAirs At prophAse, indicAting thAt AurorA-A is essentiAl for proper sepArAtion of centriole pAirs. When we injected Anti-AurorA-A Antibodies into prometAphAse cells thAt hAd sepArAted their centriole pAirs, chromosomes were severely misAligned on the metAphAse plAte, indicAting thAt AurorA-A is required for proper movement of chromosomes on the metAphAse plAte. Furthermore, inhibition of AurorA-A At metAphAse by microinjected Antibodies prevented cells from completing cytokinesis, suggesting thAt AurorA-A Also hAs importAnt functions in lAte mitosis. These results strongly suggest thAt AurorA-A is essentiAl for mAny cruciAl events during mitosis And thAt the phosphorylAtion of A series of substrAtes by AurorA-A At different stAges of mitosis mAy promote diverse criticAl events in mitosis to mAintAin chromosome integrity in humAn cells.
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roles of AurorA A kinAse in mitotic entry And g2 checkpoint in mAmmAliAn cells
Genes to Cells, 2002Co-Authors: Tomotoshi Marumoto, Toru Hirota, Dongwei Zhang, Tetsuro Morisaki, Naoko Kunitoku, Yasuko Ichikawa, Takashi Sasayama, Shinji KuninakaAbstract:BAckground: VArious mitotic events Are controlled by Cdc2-cyclin B And other mitotic kinAses. AurorA/Ipl1-relAted mitotic kinAses were proved to plAy key roles in mitotic progression in diverse lower orgAnisms. AurorA-A is A mAmmAliAn counterpArt of AurorA/Ipl1-relAted kinAses And is thought to be A potentiAl oncogene. However, the regulAtion of AurorA-A ActivAtion And the commitment of AurorA-A in the progression of G2-M phAse Are lArgely unknown in mAmmAliAn cells. Results: We demonstrAted thAt AurorA-A is ActivAted depending on the ActivAtion of Cdc2-cyclin B in mAmmAliAn cells. Since Cdc2-cyclin B does not directly phosphorylAte AurorA-A, indirect pAthwAys such As the inhibition of PP1 by Cdc2-cyclin B mAy Act for the ActivAtion of AurorA-A kinAse. Microinjection of Anti-AurorA-A Antibodies into HeLA cells At lAte G2 phAse cAused A significAnt delAy in mitotic entry. Furthermore, AurorA-A ActivAtion At G2-M trAnsition wAs inhibited by DNA dAmAge, And the over-expression of AurorA-A induced the AbrogAtion of the DNA dAmAge-induced G2 checkpoint. Conclusions: AurorA-A is ActivAted downstreAm of Cdc2-cyclin B And plAys cruciAl roles in proper mitotic entry And G2 checkpoint control. DysregulAtion of AurorA-A induces AbnormAl G2-M trAnsition in mAmmAliAn cells And mAy leAd to chromosome instAbility, which results in the development And progression of mAlignAnt tumours.
