Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C35H30N4O4 |
Molecular Weight | 570.6371 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[H][C@]12C[C@H]([C@@H](OC)[C@](C)(O1)N3C4=CC=CC=C4C5=C6CNC(=O)C6=C7C8=C(C=CC=C8)N2C7=C35)N(C)C(=O)C9=CC=CC=C9
InChI
InChIKey=BMGQWWVMWDBQGC-IIFHNQTCSA-N
InChI=1S/C35H30N4O4/c1-35-32(42-3)25(37(2)34(41)19-11-5-4-6-12-19)17-26(43-35)38-23-15-9-7-13-20(23)28-29-22(18-36-33(29)40)27-21-14-8-10-16-24(21)39(35)31(27)30(28)38/h4-16,25-26,32H,17-18H2,1-3H3,(H,36,40)/t25-,26-,32-,35+/m1/s1
Molecular Formula | C35H30N4O4 |
Molecular Weight | 570.6371 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/10454207Curator's Comment: description was created based on several sources, including:
https://www.novartis.com/news/media-releases/novartis-drug-pkc412-midostaurin-granted-fda-priority-review-newly-diagnosed | http://adisinsight.springer.com/drugs/800002524
Sources: https://www.ncbi.nlm.nih.gov/pubmed/10454207
Curator's Comment: description was created based on several sources, including:
https://www.novartis.com/news/media-releases/novartis-drug-pkc412-midostaurin-granted-fda-priority-review-newly-diagnosed | http://adisinsight.springer.com/drugs/800002524
Midostaurin, a derivate of staurosporine (N-benzoylstaurosporine), is a broad-spectrum inhibitor of Ser/Thr and Tyr protein kinases. Midostaurin showed broad antiproliferative activity against various tumor and normal cell lines in vitro and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. Midostaurin showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. At the end of 2016 FDA granted Priority Review to the PKC412 (midostaurin) new drug application (NDA) for the treatment of acute myeloid leukemia (AML) in newly-diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM).
Originator
Sources: https://www.google.com/patents/US5093330
Curator's Comment: https://www.ncbi.nlm.nih.gov/pubmed/2714889
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2034796 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12124173 |
528.0 nM [IC50] | ||
Target ID: ETV6-NTRK3 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23131561 |
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Target ID: P04409 Gene ID: 282001.0 Gene Symbol: PRKCA Target Organism: Bos taurus (Bovine) Sources: https://www.ncbi.nlm.nih.gov/pubmed/10454207 |
27.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | RYDAPT Approved UseRYDAPT is a kinase inhibitor indicated for the treatment of adult patients with:
Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation Launch Date2017 |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
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Analogs of staurosporine: potential anticancer drugs? | 1998 Nov |
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Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. | 2002 Feb |
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Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. | 2002 Jun |
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Prostacyclin production in rat aortic smooth muscle cells: role of protein kinase C, phospholipase D and cyclooxygenase-2 expression. | 2003 Nov 1 |
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Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. | 2004 Nov |
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FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. | 2005 Dec 15 |
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Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells. | 2007 Jul 15 |
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Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells. | 2009 Sep |
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Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
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H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells. | 2010 Oct |
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Midostaurin (PKC412) modulates differentiation and maturation of human myeloid dendritic cells. | 2010 Sep |
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Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. | 2011 |
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Effects of the protein kinase inhibitor PKC412 on gene expression and link to physiological effects in zebrafish Danio rerio eleuthero-embryos. | 2011 Jan |
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Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia. | 2011 Oct 27 |
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Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. | 2011 Oct 27 |
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Comprehensive analysis of kinase inhibitor selectivity. | 2011 Oct 30 |
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Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. | 2011 Oct 30 |
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A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. | 2013 Apr 15 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22627678
50 mg twice daily for 14 days
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23131561
100 nM PKC412 treatment for 24 h induced the activation of caspase-3 and subsequently inactive the activity of PARP. Moreover, PKC412 treatment showed the inhibition of survivin, XIAP and Bcl-2 expression. The PKC412-induced apoptosis is further supported by the morphology findings that PKC412 treatment show the DNA damage and appearance of apoptotic bodies in IMS-M2 cells.
Substance Class |
Chemical
Created
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Record UNII |
ID912S5VON
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Record Status |
Validated (UNII)
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NCI_THESAURUS |
C1742
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EU-Orphan Drug |
EU/3/10/765
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FDA ORPHAN DRUG |
306410
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WHO-ATC |
L01XE39
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NCI_THESAURUS |
C2089
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NDF-RT |
N0000175605
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FDA ORPHAN DRUG |
285909
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656576
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7677
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Midostaurin
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m7534
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DTXSID40923522
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Midostaurin
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