生物活性

• 描述PKC412, a prototype kinase inhibitor, was originally identified as an inhibitor preferentially against PKC (protein kinase C), with IC50 values of 22 nM, 24 nM, 30 nM, 31 nM, 160 nM and 330 nM for PKCα, PKCγ, PKCβ1, PKCβ2, PKCη and PKCδ, respectively, and subsequently shown as a multi-target inhibitor with IC50 values of 38 nM, 86 nM, 95 nM, 390 nM, 570 nM, 570 nM, 790 nM, 800 nM, 912 nM, 1.1 μM, 1.25 μM and 1.9 μM for PPK, KDR, c-Syk, Flk1, CDK1/CyclinB, PKA, c-FGR, c-Src, FLT1, EGFR, PKCε, Myosin-light chain kinase (measured by recombinant enzymatic activity)^[1]. PKC412 showed anti-proliferatively active in T-24, HL-60 and bovine corneal endothelial cell lines with IC50 values of 0.029μM, 0.13μM and 0.022μM, respectively. In the presence of PKC412 with concentration ranged from 0.1μM to 10μM, the release of H202 induced by PMA, the activator of PKC, in monocytes was decreased in a concentration-dependent manner. PKC412 showed more potent anti-tumor activity than staurosporine against T-24 bladder carcinoma xenografts in athymic nude mice^[2]. For recently it was found that PKC412 was a potent inhibitor of FLT3 tyrosine kinase and has activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drived advanced systemic mastocytosis. PKC412 was in development in approval for treating acute myeloid leukemia and advanced systemic mastocytosis^[3].
• 作用机制PKC412 is a derivative of staurosporine, which is an ATP-competitive inhibitor of PKC^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A172 cell	-	Growth inhibition assay	-	Inhibition of human A172 cell growth in a cell viability assay, IC50=0.2915 μM	SANGER
  A204 cell	-	Growth inhibition assay	-	Inhibition of human A204 cell growth in a cell viability assay, IC50=0.10052 μM	SANGER
  A375 cells	-	Cytotoxicity assay	72 h	Toxicity against human A375 cells after 72 hrs by cell titer-blue assay, IC50=0.18 μM	19654408

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• 动物研究
  剂量	Mice[4] (p.o.): 5 mg/kg, max = 1000 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dogs[5] Dose 10 mg/kg 3 mg/kg Administration p.o. p.o. Cmax 46.6 ng/ml 144 ng/ml T1/2 10 h 9.6 h F 0.093 0.485 AUClast 1640 ng·h/ml Tmax 4 - 8 h 4 h AUCinf 946 ng·h/ml 1660 ng·h/ml

• 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
  NCT03680677	Leukemia, Acute ... more >> MDS Collapse <<	Not Applicable	Not yet recruiting	November 2025	United States, Pennsylvania ... more >> Abramson Cancer Center of the University of Pennsylvania Not yet recruiting Philadelphia, Pennsylvania, United States, 19104 Collapse <<
  NCT02665065	Acute Myeloid Leukemia ... more >> Leukemia, Acute Myeloid Myeloid Leukemia, Acute Leukemia, Myeloid, Acute Acute Myelogenous Leukemia Leukemia, Acute Myelogenous Myelogenous Leukemia, Acute Collapse <<	Phase 3	Recruiting	June 2020	United States, Arizona ... more >> Banner MD Anderson Cancer Center Recruiting Gilbert, Arizona, United States United States, Connecticut Yale Cancer Center Recruiting New Haven, Connecticut, United States United States, Florida Mayo Clinic Recruiting Jacksonville, Florida, United States United States, Illinois Loyola University Medical Center Recruiting Maywood, Illinois, United States United States, Kansas The University of Kansas Cancer Center Recruiting Westwood, Kansas, United States United States, Minnesota Mayo Clinic Recruiting Rochester, Minnesota, United States United States, Missouri Washington University School of Medicine Recruiting Saint Louis, Missouri, United States United States, Nebraska University of Nebraska Medical Center Recruiting Omaha, Nebraska, United States United States, New York Roswell Park Cancer Institute Recruiting Buffalo, New York, United States Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States Stony Brook University Recruiting Stony Brook, New York, United States United States, Ohio University Hospital of Cleveland Seidman Cancer Center Recruiting Cleveland, Ohio, United States The Ohio State University Comprehensive Cancer Center Recruiting Columbus, Ohio, United States United States, Texas Baylor Charles A. Sammons Cancer Center Recruiting Dallas, Texas, United States MD Anderson Cancer Center Recruiting Houston, Texas, United States United States, Washington Fred Hutchinson Cancer Research Center Recruiting Seattle, Washington, United States United States, Wisconsin Medical College of Wisconsin Recruiting Milwaukee, Wisconsin, United States Canada, Ontario University of Ottawa Recruiting Ottawa, Ontario, Canada 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 <<

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• 参考文献

• [1] Fabbro D, Buchdunger E, et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. Pharmacol Ther. 1999 May-Jun;82(2-3):293-301.

  [2] Meyer T, Regenass U, et al. RETRACTED ARTICLEA derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989 May 15;43(5):851-6.

  [3] Gotlib J, Kluin-Nelemans HC, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41.

  [4] Pharmacodynamic studies of midostaurin

  [5] PK parameters of PKC412

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