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
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

1. 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.
2. Clinical trial number NCT00651261 for "Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia" at ClinicalTrials.gov
3. 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.
4. 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.