生物活性

• 靶点

  FLT3 IC50:4.2nM

  FLT3 (ITD) IC50:1.1nM

• 描述The receptor tyrosine kinase of FLT3 is thought as implicating driver of acute myeloid leukemia (AML) due to the presence ratio of 30% for activated mutations found in AML patients. Quizartinib is the second-generation FLT3 inhibitor with binding affinity of Kd value of 1.6nM, and with IC50 values of 1.1nM, 4.2nM and 0.56nM for internal tandem duplications (ITDs) type or wild type of FLT3 autophosphorylation and MV4-11 cells proliferation, respectively. Quizartinib at concentration of 10μM demonstrated the highest affinity to FLT3 in a primary screen of 402 kinases. In a mice model orally administrated with Quizartinib at dose of 10mg/kg, a better absorption achieving at peak plasma concentration of 3.8μM within 2 hours was observed, and a concentration closing to its cellular IC50 value remained even after 24 hours. The peak concentration could be elevated to about 25μM at doses ranging from 0.1 to 100 mg/kg in a single-dose pattern. The highest plasma concentration achieved at dose ranging in 100-300mg/kg. When treated with Quizartinib at dose of 10mg/kg, 90% inhibition of FLT3 activity within 2 hours and 40% inhibition within 24 hour could be observed in a MV4-11 tumor xenograft model. Furthermore, no obvious signs of toxicity, including weight loss, was observed during 60-day period, suggesting the rapid and complete regression of this compound in tumor models. In primary AML cells, IC50 values of FLT3 autophosphorylation and cell viability were 2nM and 0.3nM, respectively, suggesting a well effect on cell survival . Quizartinib could significantly inhibit cell viability, cell growth, and induce cell apotosis in different cell lines with IC50 values ranging from 0.1 to 7248nM.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  8226/MR20	0.1-10 μM	Function Assay	30 min	enhances uptake of substrates of ABCG2 and ABCB1 in a concentration-dependent manner	23967177
  8226/MR20	0.1 µM	Cell Viability Assays	96 h	sensitizes K562/ABCG2 cells to mitoxantrone topotecan	23967177
  A375	-	Growth Inhibition Assay	72 h	IC50> 10 000 nM	19654408

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• 动物研究
  剂量	Nonhuman primates: 10 mg/kg - 200 mg/kg[3] (p.o.) Mice: 1 mg/kg, 10 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice Dose 10 mg/kg Administration p..o. Cmax 3.8 ± 0.4 μM Tmax 1.5 ± 0.9 h AUC0→24h 35 ± 4 μM·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
  NCT01390337	Leukemia, Myeloid, Acute	Phase 1	Completed	-	United States, Florida ... more >> Mayo Clinic Jacksonville Jacksonville, Florida, United States, 32224 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 United States, Maryland Johns Hopkins Medical Institute Baltimore, Maryland, United States, 21231 United States, New York Memorial-Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Texas M.D. Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT02428543	Acute Myeloid Lukemia	Phase 1 Phase 2	Recruiting	September 2020	France ... more >> Dr Abdelaziz CHAIB Recruiting Aix-en-Provence, France, 13600 Contact: Abdelaziz CHAIB       achaib@ch-aix.fr    Principal Investigator: Abdelaziz CHAIB          Chu Amiens Recruiting Amiens, France, 80054 Contact: MAROLLEAU Jean Pierre          Principal Investigator: MAROLLEAU Jean Pierre          CHU d'Angers Recruiting Angers, France, 49033 Contact: Martine GARDEMBAS       Magardembas@chu-angers.fr    Principal Investigator: Martine GARDEMBAS          Hôpital VICTOR DUPOUY Recruiting Argenteuil, France, 95107 Contact: AL JIJAKLI Ahmad       ahmad.aljijakli@ch-argenteuil.fr    Principal Investigator: AL JIJAKLI Ahmad          Dr Edouard RANDIAMALALA Recruiting Bayonne, France, 64100 Contact: Edouard RANDIAMALALA       erandiamalala@ch-cotebasque.fr    Principal Investigator: Edouard RANDIAMALALA          CHU de Besançon Recruiting Besançon, France, 25030 Contact: Fabrice LAROSA       flarosa@chu-besançon.fr    Principal Investigator: Fabrice LAROSA          Dr Thorsten BRAUN Recruiting Bobigny, France, 93000 Contact: Thorsten BRAUN       thorsten.braun@aphp.fr    Principal Investigator: Thorsten BRAUN          CHU Boulogne Sur Mer Recruiting Boulogne Sur Mer cedex, France, 62321 Contact: CHOUFI Bachra       b.choufi@ch-boulogne.fr    Principal Investigator: CHOUFI Bachra          Chr Clemenceau Recruiting Caen Cedex, France, 14033 Contact: REMAN Oumédaly       reman-o@chu-caen.fr    Principal Investigator: REMAN Oumédaly          Hôpital d'Instruction des Armées PERCY Recruiting Clamart, France, 92141 Contact: Jean Valère MALFUSSON       jvmalf@free.fr    Principal Investigator: Jean Valère MALFUSSON          Dr Stéphanie HAÏAT Recruiting Corbeil-essonnes, France, 91100 Contact: Stéphanie HAÏAT          Principal Investigator: Stéphanie HAÏAT          Hôpital Henri Mondor Recruiting Créteil, France, 94010 Contact: PAUTAS Cécile       cecile.pautas@hmn.aphp.fr    Principal Investigator: PAUTAS Cécile          CHU de Dijon Not yet recruiting Dijon, France, 21079 Contact: CAILLOT Denis       denis.caillot@chu-dijon.fr    Principal Investigator: CAILLOT Denis          Centre hospitalier de Versailles Recruiting Le Chesnay cedex, France, 78157 Contact: Rousselot Philippe    003339638622    phrousselot@ch-versailles.fr    Principal Investigator: Rousselot Philippe          Hôpital Claude Huriez Recruiting Lille cedex, France, 59037 Contact: QUESNEL Bruno       bquesnel@chru-lille.fr    Principal Investigator: QUESNEL Bruno          CHRU Dupuytren Not yet recruiting Limoges cedex, France, 87042 Contact: TURLURE Pascal       pascal.turlure@chu-limoges.fr    Principal Investigator: TURLURE Pascal          Hôpital Edouard Herriot Recruiting Lyon cedex 03, France, 69437 Contact: THOMAS Xavier       xavier.thomas@chu-lyon.fr    Principal Investigator: THOMAS Xavier          Dr Regis COSTELLO Recruiting Marseille, France, 13000 Contact: Regis COSTELLO       regis.costello@ap-hm.fr    Principal Investigator: Regis COSTELLO          Centre Hospitalier de Meaux Recruiting Meaux, France, 77104 Contact: FRAYFER Jamilé       j-frayfer@ch-meaux.fr    Principal Investigator: FRAYFER Jamilé          Dr Mario OJEDA-URIBE Recruiting Mulhouse, France, 68000 Contact: Mario OJEDA-URIBE       ojedam@ch-mulhouse.fr    Principal Investigator: Mario OJEDA-URIBE          Dr Jacques DELAUNAY Recruiting Nantes, France, 44000 Contact: Jacques DELAUNAY       jacques.delaunay@chu-nantes.fr    Principal Investigator: Jacques DELAUNAY          CHU Nice, Hôpital Archet 1 Recruiting Nice cedex 3, France, 06202 Contact: MANNONE Lionel       mannone.l@chu-nice.fr    Principal Investigator: MANNONE Lionel          CHU de Nîmes Recruiting Nîmes, France, 30029 Contact: Eric JOURDAN       eric.jourdan@chu-nimes.fr    Principal Investigator: Eric Jourdan          Hôpital Saint Antoine Recruiting Paris cedex 12, France, 75751 Contact: ISNARD Françoise       francoise.isnard@sat.aphp.fr    Principal Investigator: ISNARD Françoise          Hôpital Necker Enfants Malades Recruiting Paris cedex 15, France, 75743 Contact: SUAREZ Felipe       felipe.suarez@nck.aphp.fr    Principal Investigator: SUAREZ Felipe          Hôpital Saint Louis Recruiting Paris, France, 75010 Contact: RAFFOUX Emmanuel       emmanuel.raffoux@sls.ap-hop-paris.fr    Principal Investigator: RAFFOUX Emmanuel          Hôpital La Pitié Salpêtrière Recruiting Paris, France, 75013 Contact: UZUNOV Madalina       madalina.uzunov@psl.aphp.fr    Principal Investigator: UZUNOV Madalina          Dr Laurence SANHES Suspended Perpignan, France, 66000 Dr Arnaud PIGNEUX Recruiting Pessac, France, 33604 Contact: Arnaud PIGNEUX       arnaud.pigneux@chu-bordeaux.fr    Principal Investigator: Arnaud PIGNEUX          Centre Hospitalier René Dubos Recruiting Pontoise Cedex, France, 95303 Contact: VAIDA Iona Dana       ioana.vaida@ch-pontoise.fr    Principal Investigator: VAIDA Iona Dana          Marc BERNARD Recruiting Rennes, France, 35000 Contact: Marc BERNARD       marc.bernard@chu-rennes.fr    Principal Investigator: Marc BERNARD          Dr Emilie LEMASLE Recruiting Rouen, France, 76000 Contact: Emilie LEMASLE       emilie.lemasle@chb.unicancer.fr    Principal Investigator: Emilie LEMASLE          Centre Hospitalier René Huguenin Suspended Saint Cloud, France, 92210 Institut de Cancérologie de la Loire Recruiting Saint-Priest-en-Jarez, France, 42270 Contact: Emmanuelle TAVERNIER-TARDY       emmanuelle.tavernier@icloire.fr    Principal Investigator: Emmanuelle TAVERNIER-TARDY          Dr Réda GARIDI Recruiting Saint-Quentin, France, 02100 Contact: Réda GARIDI          Principal Investigator: Réda GARIDI          Dr Christian RECHER Recruiting Toulouse, France, 31000 Contact: Christian RECHER          Principal Investigator: Christian RECHER          Centre Hospitalier de Valenciennes Recruiting Valenciennes, France, 59322 Contact: FERNANDES José       fernandes-j@ch-valenciennes.fr    Principal Investigator: FERNANDES José Collapse <<
  NCT00462761	Acute Myeloid Leukemia ... more >> Leukemia Myelodysplastic Syndrome AML MDS Collapse <<	Phase 1	Completed	-	United States, Alabama ... more >> University of Alabama at Birmingham Birmingham, Alabama, United States, 35294 United States, Nebraska University of Nebraska Medical Center Omaha, Nebraska, United States, 68198 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Georgia Chemotherapy and Immunotherapy Clinic T'Bilisi, Georgia Hematology and Chemotherapy Clinic T'bilisi, Georgia Collapse <<

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