7-HYDROXYSTAUROSPORINE

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H26N4O4
Molecular Weight	482.5304
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n3c4ccccc4c5c6[C@@H](O)NC(=O)c6c7c8ccccc8n2c7c35

InChI

InChIKey=PBCZSGKMGDDXIJ-HQCWYSJUSA-N

InChI=1S/C28H26N4O4/c1-28-25(35-3)15(29-2)12-18(36-28)31-16-10-6-4-8-13(16)19-21-22(27(34)30-26(21)33)20-14-9-5-7-11-17(14)32(28)24(20)23(19)31/h4-11,15,18,25,27,29,34H,12H2,1-3H3,(H,30,33)/t15-,18-,25-,27-,28+/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/3429345
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT00082017 | https://clinicaltrials.gov/ct2/show/NCT00045513 | https://clinicaltrials.gov/ct2/show/NCT00072189 | https://clinicaltrials.gov/ct2/show/NCT00072267 | https://www.ncbi.nlm.nih.gov/pubmed/20943405 | https://www.ncbi.nlm.nih.gov/pubmed/17850214

7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor which is under development as an anti-cancer agent in the USA and Japan. Although UCN-01 was originally isolated from the culture broth of Streptomyces sp. as a protein kinase C-selective inhibitor, its ultimate target as an anti-cancer agent remains elusive. As a single agent, UCN-01 exhibits two key biochemical effects, namely accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Both these effects may be important for its anti-cancer activity. As a modulator, 7-Hydroxystaurosporine enhances the cytotoxicity of other anti-cancer drugs such as DNA-damaging agents and anti-metabolite drugs through putative abrogation of G2 and/or S phase accumulation induced by these anti-cancer agents. 7-Hydroxystaurosporine had been in phase II clinical trials Life Sciences for the treatment of T-cell lymphoma, malignant melanoma, pancreatic cancer, small cell lung cancer, acute myeloid leukemia, ovarian cancer. However, the research was either discontinued or suspended.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase Chk1 23 Target ID: CHEMBL4630 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20943405	Inhibitor 8504	5.6 nM [IC50]
Serine/threonine-protein kinase Chk2 9 Target ID: CHEMBL2527 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20943405	Inhibitor 8504	10.0 nM [IC50]
3-phosphoinositide dependent protein kinase-1 7 Target ID: CHEMBL2534 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8504
Serine/threonine-protein kinase PIM3 10 Target ID: CHEMBL5407 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8504
Serine/threonine-protein kinase c-TAK1 3 Target ID: CHEMBL5600 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8504

Conditions

Condition	Modality	Highest Phase	Product
T-cell lymphoma 3 Sources: https://clinicaltrials.gov/ct2/show/NCT00082017	Primary	Phase II 1147	Unknown Approved Use Unknown
Fallopian tube cancer 17 Sources: https://clinicaltrials.gov/ct2/show/NCT00072267	Primary	Phase II 1147	Unknown Approved Use Unknown
Ovarian cancer 160 Sources: https://clinicaltrials.gov/ct2/show/NCT00072267	Primary	Phase II 1147	Unknown Approved Use Unknown
Recurrent melanoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00072189	Primary	Phase II 1147	Unknown Approved Use Unknown
Leukemia 72 Sources: https://clinicaltrials.gov/ct2/show/NCT00045513	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
36.8 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
36.4 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	42.5 mg/m² 1 times / day multiple, intravenous dose: 42.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
19.1 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15501960	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.8 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	70 mg/m² single, intravenous dose: 70 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.6 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	90 mg/m² single, intravenous dose: 90 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
24510 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
21212 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	42.5 mg/m² 1 times / day multiple, intravenous dose: 42.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
26140 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15501960	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10157 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	70 mg/m² single, intravenous dose: 70 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12526 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	90 mg/m² single, intravenous dose: 90 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
559 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
618 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11304786	42.5 mg/m² 1 times / day multiple, intravenous dose: 42.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
509 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15501960	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
280.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	70 mg/m² single, intravenous dose: 70 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
341.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17429623	90 mg/m² single, intravenous dose: 90 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: IRINOTECAN	IRINOTECAN	7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.829% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15501960	53 mg/m² 1 times / day multiple, intravenous dose: 53 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		7-HYDROXYSTAUROSPORINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
53 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 53 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 53 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	DLT: hyperglycemia, nausea... Dose limiting toxicities: hyperglycemia (11.1%) nausea (11.1%) vomiting (11.1%) Pulmonary toxicity (11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/11304786
90 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 90 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/17429623	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17429623	DLT: hypophosphatemia... Dose limiting toxicities: hypophosphatemia (grade 3, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/17429623
70 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 70 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 70 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/17429623	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17429623	Sources: https://pubmed.ncbi.nlm.nih.gov/17429623
42.5 mg/m2 1 times / day multiple, intravenous RP2D Dose: 42.5 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 42.5 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	DLT: hyperglycemia... Dose limiting toxicities: hyperglycemia (grade 3, 9%) Sources: https://pubmed.ncbi.nlm.nih.gov/11304786

AEs

AE	Significance	Dose	Population
Pulmonary toxicity	11.1% DLT	53 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 53 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 53 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786
hyperglycemia	11.1% DLT	53 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 53 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 53 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786
nausea	11.1% DLT	53 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 53 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 53 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786
vomiting	11.1% DLT	53 mg/m2 1 times / day multiple, intravenous Highest studied dose Dose: 53 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 53 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786
hypophosphatemia	grade 3, 50% DLT, Disc. AE	90 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 90 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/17429623	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17429623
hyperglycemia	grade 3, 9% DLT	42.5 mg/m2 1 times / day multiple, intravenous RP2D Dose: 42.5 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 42.5 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11304786	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/11304786

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY34402	https://www.001chemical.com/chem/search?q=DY34402
1PlusChem LLC	1P0015QU	https://www.1pchem.com/search?query=1P0015QU
1PlusChem LLC	1P008UIN	https://www.1pchem.com/search?query=1P008UIN
Angene	AGN-PC-0P46YU	http://www.angenechemical.com/productshow/AGN-PC-0P46YU.html
ApexBio Technology	C4783	https://www.apexbt.com/catalogsearch/result/?q=C4783
Cayman Chemical	18130	http://www.caymanchem.com/app/template/Product.vm/catalog/18130
eMolecules	29914465	https://orderbb.emolecules.com/search/#?query=29914465
Matrix Scientific	152576	http://www.matrixscientific.com/152576.html
Molcore	MC34402	http://www.molcore.com/CatMC34402.html
MuseChem	M019098	https://www.musechem.com/product/M019098.html
Wonderchem	WD04XAF	http://www.wonder-chem.com/search.html?text=WD04XAF

PubMed

Title	Date	PubMed
Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells.	2015-12-05	26456889
Induction of DNA damage and G2 cell cycle arrest by diepoxybutane through the activation of the Chk1-dependent pathway in mouse germ cells.	2015-03-16	25633853
Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity.	2013-10	23897988
Progesterone and DNA damage encourage uterine cell proliferation and decidualization through up-regulating ribonucleotide reductase 2 expression during early pregnancy in mice.	2012-05-04	22403396
The ToxTracker assay: novel GFP reporter systems that provide mechanistic insight into the genotoxic properties of chemicals.	2012-01	22003191
ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: potential basis for the UV protective effects of caffeine.	2009-07	19242509
Phospho-p70S6K/p85S6K and cdc2/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy.	2009-03-01	19223503
p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.	2007-02	17292828
Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways.	2006-02-01	16178010
Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.	2005-11	16319524
Molecular basis for G2 arrest induced by 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine and consequences of checkpoint abrogation.	2005-08-01	16061671
A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines.	2005-08	16012789
Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways.	2005-03	15767555
Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide.	2004-10	15486189
The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors.	2003-12	14653808
Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine).	2002-03-07	11896604
UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.	2001-06	11378265
Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia.	2000-07-15	10887097
The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1.	2000-04-15	10786669
Comparison of the efficacy of 7-hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines.	1999-12-01	10571245
Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue.	1994-06	8022414
Comparison of effects of protein kinase C inhibitors on phorbol ester-induced CD4 down-regulation and augmentation of human immunodeficiency virus replication in human T cell lines.	1989-10-16	2508637
UCN-01, a selective inhibitor of protein kinase C from Streptomyces.	1987-12	3429345

Patents

Sample Use Guides

In Vivo Use Guide

Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 28 days.

Route of Administration: Intravenous

In Vitro Use Guide

The three different human HCC cell lines (HepG2, Hep3B, and Huh7) were grown at 37°C in the presence of 5% CO2 in Dulbecco's modified Eagle's media (DMEM) supplemented with 10% foetal bovine serum (FBS). The cells were seeded in a 96-well dish to a final concentration of 1×10^4 cells/well and incubated in DMEM containing 10% FCS overnight. After incubation with different concentrations of the tested compounds (7-Hydroxystaurosporine) for 72 h, the cells were incubated for 2 h with DMEM containing 0.4 mg/ml MTT. The conversion of MTT to formazan in metabolically viable cells was measured at 490 nm absorbance in a 96-well microtiter plate reader.

Name

Type

Language

KRX-0601

Preferred Name

English

7-HYDROXYSTAUROSPORINE

Common Name

English

NSC-638850

Code

English

UCN-01

Code

English

UCN-02

Code

English

7-Hydroxystaurosporine [WHO-DD]

Common Name

English

9,13-EPOXY-1H,9H-DIINDOLO(1,2,3-GH:3',2',1'-LM)PYRROLO(3,4-J)(1,7)BENZODIAZONIN-1-ONE, 2,3,10,11,12,13-HEXAHYDRO-3-HYDROXY-10-METHOXY-9-METHYL-11-(METHYLAMINO)-, (3R,9S,10R,11R,13R)-

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1404