Midostaurin

Midostaurin

Clinical data
Trade names	Rydapt
Other names	PKC412, 4'-N-benzoylstaurosporine
AHFS/Drugs.com	Monograph
Routes of administration	By mouth
ATC code	L01EX10(WHO)
Legal status
Legal status	AU:S4(Prescription only) CA:℞-only US:℞-only EU:Rx-only
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
CAS Number	120685-11-2
PubChemCID	9829523
IUPHAR/BPS	5702
DrugBank	DB06595
ChemSpider	8005258
UNII	ID912S5VON
KEGG	D05029
ChEMBL	ChEMBL608533
CompTox Dashboard(EPA)	DTXSID40923522
Chemical and physical data
Formula	C35H30N4O4
Molar mass	570.649g·mol−1
3D model (JSmol)	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,sold under the brand nameRydaptbyNovartis,is a multi-targetedprotein kinase inhibitorthat has been investigated for the treatment ofacute myeloid leukemia(AML),myelodysplastic syndrome(MDS) and advancedsystemic mastocytosis.It is a semi-synthetic derivative ofstaurosporine,analkaloidfrom the bacteriumStreptomycesstaurosporeus.

The USFood and Drug Administration(FDA) considers it to be afirst-in-class medication.

AML and MDS

Midostaurin was found to be active against oncogenicCD135(FMS-like tyrosine kinase 3 receptor, FLT3), in preclinical studies.Clinical trials have primarily focused on relapsed/refractoryAML and MDS and have included single agent and combination agent studies. After successful Phase IIclinical trials,midostaurin was found to prolong survival of FLT3-mutated AML patients when combined with conventionalinductionand consolidation therapies in a randomized Phase III clinical trial.On 28 April 2017, midostaurin was approved by the FDA for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

Systemic mastocytosis

Over 95% of patients with adult onset systemicmastocytosisand approximately 40% of children withcutaneousmastocytosis are positive for the D816Vc-Kitactivating mutation, which renders c-Kit resistant to currently available tyrosine kinase inhibitors. Midostaurin is an investigational treatment in patients with advanced forms of systemic mastocytosis and D816V c-Kit mutation with a subset of patients achieving clinical response. In anopen-label studyof 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 variantmast cell leukemia.

Side effects

Common side effects include immune system related problems (fever,febrile neutropenia),blood clottingproblems (bruising, nosebleed), and unspecific symptoms such as diarrhea,nauseaand headache.Upper respiratory tract infectionscan be dangerous.