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

[H][C@]12C[C@@H](NC)[C@@H](OC)[C@](C)(O1)N3C4=C(C=CC=C4)C5=C6[C@@H](O)NC(=O)C6=C7C8=CC=CC=C8N2C7=C35

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

Molecular Formula	C28H26N4O4
Molecular Weight	482.5304
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

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 20 Target ID: CHEMBL4630 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20943405	Inhibitor 8297	5.6 nM [IC50]
Serine/threonine-protein kinase Chk2 9 Target ID: CHEMBL2527 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20943405	Inhibitor 8297	10.0 nM [IC50]
3-phosphoinositide dependent protein kinase-1 7 Target ID: CHEMBL2534 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297
Serine/threonine-protein kinase PIM3 9 Target ID: CHEMBL5407 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297
Serine/threonine-protein kinase c-TAK1 3 Target ID: CHEMBL5600 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
T-cell lymphoma 3 Sources: https://clinicaltrials.gov/ct2/show/NCT00082017	Primary	Phase II 1132	Unknown Approved Use Unknown
Fallopian tube cancer 17 Sources: https://clinicaltrials.gov/ct2/show/NCT00072267	Primary	Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: https://clinicaltrials.gov/ct2/show/NCT00072267	Primary	Phase II 1132	Unknown Approved Use Unknown
Recurrent melanoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00072189	Primary	Phase II 1132	Unknown Approved Use Unknown
Leukemia 87 Sources: https://clinicaltrials.gov/ct2/show/NCT00045513	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
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
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
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
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

AUC

Value	Dose	Co-administered	Analyte	Population
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
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
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
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

T_1/2

Value	Dose	Co-administered	Analyte	Population
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
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
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
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

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 Page: p.2329	unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329	DLT: Pulmonary toxicity, nausea... Dose limiting toxicities: Pulmonary toxicity (11.1%) nausea (11.1%) hyperglycemia (11.1%) vomiting (11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329
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 Page: p.6	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6	DLT: hypophosphatemia... Dose limiting toxicities: hypophosphatemia (grade 3, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6
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 Co-administed with:: irinotecan(60 mg/m(2) IV irinotecan on days 1 and 8 in a 21-day cycle) Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6	Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6
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 Page: p.2322	unhealthy, ADULT n = 11 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2322	DLT: hyperglycemia... Dose limiting toxicities: hyperglycemia (grade 3, 9%) Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2322

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 Page: p.2329	unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329
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 Page: p.2329	unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329
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 Page: p.2329	unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329
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 Page: p.2329	unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2329
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 Page: p.6	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/17429623 Page: p.6
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 Page: p.2322	unhealthy, ADULT n = 11 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/11304786 Page: p.2322

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
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
eMolecules	29914465	https://orderbb.emolecules.com/search/#?query=29914465

PubMed

Title	Date	PubMed
UCN-01, a selective inhibitor of protein kinase C from Streptomyces.	1987 Dec	3429345
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 Oct 16	2508637
Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue.	1994 Jun	8022414
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 Dec 1	10571245
The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1.	2000 Apr 15	10786669
Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia.	2000 Jul 15	10887097
UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.	2001 Jun	11378265
Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine).	2002 Mar 7	11896604
The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors.	2003 Dec	14653808
Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide.	2004 Oct	15486189
A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines.	2005 Aug	16012789
Molecular basis for G2 arrest induced by 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine and consequences of checkpoint abrogation.	2005 Aug 1	16061671
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 Mar	15767555
Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.	2005 Nov	16319524
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 Feb 1	16178010
p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.	2007 Feb	17292828
ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: potential basis for the UV protective effects of caffeine.	2009 Jul	19242509
Phospho-p70S6K/p85S6K and cdc2/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy.	2009 Mar 1	19223503
Induction of DNA damage and G2 cell cycle arrest by diepoxybutane through the activation of the Chk1-dependent pathway in mouse germ cells.	2015 Mar 16	25633853

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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:45:28 UTC 2023` Edited by `admin` on `Fri Dec 15 15:45:28 UTC 2023`
Record UNII	7BU5H4V94A
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

7-HYDROXYSTAUROSPORINE

Common Name

English

NSC-638850

Code

English

UCN-01

Code

English

KRX-0601

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