生物活性

• 靶点	mTOR IC50:2.8nM

• 描述The kinase mTOR, belonging to the PIKKs family, which regulate cell growth, cell survival, and autophagy, is a key target in the development of antitumor therapies. It was found that rapamycin and its analogues, the first generation of mtor inhibitor, can activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1. AZD2014 (Vistusertib) is a potent mTORC1/2 inhibitor (IC50 = 2.8 nM, measured by recombinant truncated FLAG-tagged mTOR) and displays a high level of selectivity against other members of the PIKKs [a]. Different from rapamycin, treatment with AZD2014 at 3 to 1000 nM can significantly inhibit mTOR substrates, such as pS6-S235/236, p70S6K-T389 and 4E-BP1 Thr37/46, in a dose dependent manner, as well as no AKT activation, in MCF7 cells. While effectively inhibiting signaling to S6, PRAS40 as well as feedback phosphorylation of AKT, AZD2014 can block proliferation in all cell lines, including everolimus-resistant cells and long-term estrogen-deprived (LTED) everolimus-resistant cells at concentration 200/500 nM. Treatment of 15 mg/kg AZD2014 can induce significant growth inhibition in several hormone therapy–sensitive ERb breast cancer xenograft models like MCF7 and HCC1500, as well as three patient-derived primary explant models BR0555, CTC174, and HBCx3. Up to now, AZD2014 enters Phase 1 trial in solid tumours^[1].
• 作用机制AZD2014 is a small-molecule ATP competitive inhibitor of mTOR^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HEK293 cells	-	Function assay	-	Inhibition of recombinant FLAG-tagged mTOR (1362 to 2549) (unknown origin) expressed in HEK293 cells, IC50=2.8 nM	23375793
  human MCF7 cells	-	Function assay	-	Inhibition of mTORC1 in human MCF7 cells xenografted mouse assessed as modulation substrate	23375793
  human MDA-MB-468 cells	-	Function assay	2 h	Inhibition of mTORC2 in human MDA-MB-468 cells assessed as reduction of AKT phosphorylation at Ser473 after 2 hrs, IC50=0.08 μM	23375793

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• 动物研究
  剂量	Mice[3] (p.o.): min = 3.75 mg/kg, max = 20 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[3] Dose 20 mg/kg Administration s.c. Cmax 15 μmol/L AUC 4320 μmol/L·h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02546661	Muscle Invasive Bladder Cancer	Phase 1	Recruiting	March 27, 2020	-
  NCT03334617	Non-Small Cell Lung Cancer	Phase 2	Recruiting	July 30, 2021	-
  NCT02299999	Metastatic Breast Cancer	Phase 2	Recruiting	December 2022	France ... more >> Institut de Cancérologie de l'Ouest/Paul Papin Recruiting Angers, France Contact: Mario CAMPONE, MD       mario.campone@ico.unicancer.fr    Principal Investigator: Mario CAMPONE, MD          Institut Sainte-Catherine Recruiting Avignon, France Contact: Alice Mege, MD       a.mege@isc84.org    Principal Investigator: Alice Mege, MD          Polyclinique Bordeaux Nord Aquitaine Recruiting Bordeaux, France, 33077 Contact: Nadine DOHOLLOU, MD       n.dohollou@bordeauxnord.com    Contact: Nadine DOHOLLOU, MD          Institut Bergonié Recruiting Bordeaux, France Contact: Hervé Bonnefoi, MD       h.bonnefoi@bordeaux.unicancer.fr    Principal Investigator: Hervé Bonnefoi, MD          Centre François Baclesse Recruiting Caen, France Contact: Christelle Lévy, MD       c.levy@baclesse.unicancer.fr    Principal Investigator: Christelle Lévy, MD          Centre Jean Perrin Recruiting Clermont-Ferrand, France Contact: Marie-Ange Mouret Reynier, MD       marie-ange.mouret-reynier@cjp.fr    Principal Investigator: Marie-Ange Mouret Reynier, MD          Ch Alpes Leman Not yet recruiting Contamine Sur Arve, France, 74130 Contact: Carol ALLIOT, MD       calliot@ch-alpes-leman.fr    Contact: Carol ALLIOT, MD          Centre Georges François Leclerc Recruiting Dijon, France, 21079 Contact: Nicolas Isambert, MD       nisambert@cgfl.fr    Principal Investigator: Nicolas Isambert, MD          Chd Vendee Recruiting La Roche-sur-Yon, France, 85925 Contact: Tifenn L'Haridon, MD       tifenn.lharidon@chd-vendee.fr    Contact: Tifenn L'Haridon, MD          Centre Oscar Lambret Recruiting Lille, France Contact: Nuria KOTECKI, MD          Principal Investigator: Nuria KOTECKI, MD          Chu Dupuytren Not yet recruiting Limoges, France, 87000 Contact: Laurence VENAT-BOUVET, MD       laurence.venat-bouvet@chu-limoges.fr    Contact: Laurence VENAT-BOUVET, MD          Hopital Privé Jean Mermoz Not yet recruiting Lyon, France, 69008 Contact: Olfa DERBEL, MD       o.derbelmermoz@gmail.com    Contact: Olfa DERBEL, MD          Centre Hospitalier Lyon Sud Recruiting Lyon, France Contact: Benoit You, MD          Principal Investigator: Benoit You, MD          Centre Léon Bérard Recruiting Lyon, France Contact: Thomas Bachelot, MD       thomas.bachelot@lyon.unicancer.fr    Principal Investigator: Thomas Bachelot, MD          Institut Paoli Calmettes Recruiting Marseille, France Contact: Anthony Gonçalves, MD       goncalvesa@ipc.unicancer.fr    Principal Investigator: Anthony Gonçalves, MD          Institut Régional du Cancer Montpellier Val d'Aurelle Recruiting Montpellier, France Contact: William Jacot, MD       william.jacot@icm.unicancer.fr    Principal Investigator: William Jacot, MD          Centre Alexis Vautrin Recruiting Nancy, France Contact: Elisabeth Luporsi, MD       e.luporsi@nancy.unicancer.fr    Principal Investigator: Elisabeth Luporsi, MD          Institut de Cancérologie de l'Ouest/ René Gauducheau Recruiting Nantes, France Contact: Mario Campone, MD       mario.campone@ico.unicancer.fr    Principal Investigator: Mario Campone, MD          Centre Antoine Lacassagne Recruiting Nice, France Contact: Jean-Marc Ferrero, MD       jean-marc.ferrero@nice.unicancer.fr    Principal Investigator: Jean-Marc Ferrero, MD          Institut Curie Recruiting Paris, France Contact: Marie-Paule Sablin, MD       mariepaule.sablin@curie.fr    Principal Investigator: Marie-Paule Sablin, MD          Centre Eugène Marquis Recruiting Rennes, France Contact: Claudia Lefeuvre-Plesse, MD       c.lefeuvre@rennes.unicancer.fr    Principal Investigator: Claudia Lefeuvre-Plesse, MD          Centre Henri Becquerel Recruiting Rouen, France Contact: Jean-Christophe Théry, MD          Principal Investigator: Jean-Christophe Théry, MD          Institut Curie Recruiting Saint-Cloud, France Contact: Florence COUSSY, MD       florence.coussy@curie.fr    Principal Investigator: Florence COUSSY, MD          Hopitaux Universitaire de Strasbourg - Hopital Civil Recruiting Strasbourg, France Contact: Philippe BARTHELEMY, MD       philippe.barthelemy@chru-strasbourg.fr    Principal Investigator: Philippe BARTHELEMY, MD          Hopitaux Du Leman Recruiting Thonon-les-Bains, France, 74200 Contact: Francesco DEL PIANO, MD       f-delpiano@ch-hopitauxduleman.fr    Contact: Francesco DEL PIANO, MD          Institut Claudius Regaud Recruiting Toulouse, France Contact: Florence Dalenc, MD       dalenc.florence@iuct-oncopole.fr    Principal Investigator: Florence Dalenc, MD          Gustave Roussy Recruiting Villejuif, France Contact: Monica Arnedos, MD       Monica.ARNEDOS@gustaveroussy.fr    Principal Investigator: Monica Arnedos, MD          Sub-Investigator: Fabrice André, MD Collapse <<

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• 参考文献

• [1] First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors.

  [2] Pike KG, Malagu K, et al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett. 2013 Mar 1;23(5):1212-6.

  [3] Guichard SM, Curwen J, et al. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules. Mol Cancer Ther. 2015 Nov;14(11):2508-18.