Midostaurin

Midostaurin
Clinical data


Routes of administration	Oral
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name (9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one
Synonyms	4'-N-benzoylstaurosporine
CAS Number	120685-11-2
PubChem (CID)	9829523
IUPHAR/BPS	5702
ChemSpider	8005258
UNII	ID912S5VON^Y
ChEMBL	CHEMBL608533
Chemical and physical data
Formula	C₃₅H₃₀N₄O₄
Molar mass	570.637 g/mol
3D model (Jmol)	Interactive image
SMILES C[C@@]12[C@@H]([C@@H](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC
InChI 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 Key:BMGQWWVMWDBQGC-IIFHNQTCSA-N

Midostaurin (PKC412) is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus, and is active in patients with mutations of CD135 (FMS-like tyrosine kinase 3 receptor, FLT3).^[1]

After successful Phase II clinical trials, a Phase III trial for AML has started in 2008. It is testing midostaurin in combination with daunorubicin and cytarabine.^[2] In another trial, the substance has proven ineffective in metastatic melanoma.^[3]

In an open-label study of patients with mastocytosis-related organ damage (89 eligible patients meeting inclusion for the primary efficacy population), midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia.^[4]

References

↑ Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. (2010). "Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome with Either Wild-Type or Mutated FLT3". Journal of Clinical Oncology. 28 (28): 4339–4345. doi:10.1200/JCO.2010.28.9678. PMID 20733134.
↑ Clinical trial number NCT00651261 for "Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia" at ClinicalTrials.gov
↑ Millward, M. J.; House, C.; Bowtell, D.; Webster, L.; Olver, I. N.; Gore, M.; Copeman, M.; Lynch, K.; Yap, A.; Wang, Y.; Cohen, P. S.; Zalcberg, J. (2006). "The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study". British Journal of Cancer. 95 (7): 829–834. doi:10.1038/sj.bjc.6603331. PMC 2360547. PMID 16969355.
↑ Gotlib, Jason; Kluin-Nelemans, Hanneke C.; George, Tracy I.; Akin, Cem; Sotlar, Karl; Hermine, Olivier; Awan, Farrukh T.; Hexner, Elizabeth; Mauro, Michael J. (2016-06-29). "Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis". New England Journal of Medicine. 374 (26): 2530–2541. doi:10.1056/nejmoa1513098.

Cytokine receptor modulators

Chemokine

See here instead.

CSF

Erythropoietin	Agonists: ARA-290 Asialo erythropoietin Carbamylated erythropoietin CNTO-530 Darbepoetin alfa Epoetin alfa Epoetin beta Epoetin delta Epoetin epsilon Epoetin gamma Epoetin kappa Epoetin omega Epoetin theta Epoetin zeta Erythropoietin (EPO) Erythropoietin-Fc Methoxy polyethylene glycol-epoetin beta (CERA/Mircera) Peginesatide Pegol sihematide (EPO-018B)

G-CSF (CSF3)	Agonists: Filgrastim Granulocyte colony-stimulating factor Lenograstim Leridistim Lipegfilgrastim Nartograstim Pegfilgrastim Pegnartograstim

GM-CSF (CSF2)	Agonists: Ecogramostim Granulocyte macrophage colony-stimulating factor Milodistim Molgramostim Regramostim Sargramostim Antibodies: Mavrilimumab MOR103 Namilumab

M-CSF (CSF1)	Agonists: Cilmostim Interleukin-34 Lanimostim Macrophage colony-stimulating factor Mirimostim Kinase inhibitors: Agerafenib

SCF (c-Kit)	See here instead.

Thrombopoietin	Agonists: Eltrombopag Pegacaristim Promegapoietin Romiplostim Thrombopoietin (THPO, MGDF)

Interferon

IFNAR (α/β, I)	Agonists: Albinterferon Interferon alpha (interferon alfa, IFN-α) Interferon alfa (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21) Interferon alfa 2a Interferon alfa 2b Interferon alfa n1 Interferon alfacon-1 Interferon alpha-n3 Interferon beta (IFN-β) (IFNB1, IFNB3) Interferon beta 1a Interferon beta 1b Interferon kappa (IFN-ε/κ/τ/ζ, IFNK) Interferon omega (IFN-ω, IFNW1) Peginterferon alfa-2a Peginterferon alfa-2b Antibodies: Anifrolumab Faralimomab MEDI-545 Rontalizumab Sifalimumab Decoy receptors: Bifarcept

IFNGR (γ, II)	Agonists: Interferon gamma (IFN-γ) Interferon gamma 1b Antibodies: Emapalumab Fontolizumab

IFNLR (λ, III)	See IL-28R (IFNLR) here instead.

Interleukin

See here instead.

TGFβ

See here instead.

TNF

See here instead.

Others

JAK
(inhibitors)

JAK1	Baricitinib Filgotinib Momelotinib Ruxolitinib Tofacitinib (tasocitinib, CP-690550) Upadacitinib

JAK2	AG-490 Atiprimod AZD-1480 Baricitinib CHZ868 Cucurbitacin I (elatericin B, JSI-124) CYT387 Lestaurtinib NSC-7908 NSC-33994 Pacritinib Ruxolitinib SD-1008 Tofacitinib (tasocitinib, CP-690550)

JAK3	AG-490 Cercosporamide TCS-21311 Tofacitinib (tasocitinib, CP-690550) WHI-P 154 ZM-39923 ZM-449829

Others

Additional cytokines: Cardiotrophin 1 (CT-1)
FMS-like tyrosine kinase 3 ligand (FLT3L)
Leukemia/leukocyte inhibitory factor (LIF)
Oncostatin M (OSM)
Thymic stromal lymphopoietin (TSLP)

Additional cytokine receptor modulators: Emfilermin
Lestaurtinib
Midostaurin
Quizartinib
Sorafenib
Sunitinib

See also: Peptide receptor modulators
Growth factor receptor modulators

This article is issued from Wikipedia - version of the 11/10/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.