staurosporine   

GtoPdb Ligand ID: 346

Synonyms: (+)-staurosporine | antibiotic 230 | antibiotic AM-2282
Comment: Staurosporine is a non-specific, ATP-competitive inhibitor of protein kinase C (PKC) isolated from a Streptomyces strain [9]. It inhibits all PKC enzyme isoforms [2,12], but has a more potent inhibitory effect on PKCs associated with the cell membrane compared to cytosolic PKCs.
Staurosporine analogues such as midostaurin and 7-hydroxystaurosporine are being investigated as therapeutics.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 2
Topological polar surface area 69.45
Molecular weight 466.2
XLogP 6.05
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
Canonical SMILES CNC1CC2OC(C1OC)(C)n1c3ccccc3c3c1c1n2c2ccccc2c1c1c3CNC1=O
Isomeric SMILES CN[C@@H]1C[C@H]2O[C@]([C@@H]1OC)(C)n1c3ccccc3c3c1c1n2c2ccccc2c1c1c3CNC1=O
InChI InChI=1S/C28H26N4O3/c1-28-26(34-3)17(29-2)12-20(35-28)31-18-10-6-4-8-14(18)22-23-16(13-30-27(23)33)21-15-9-5-7-11-19(15)32(28)25(21)24(22)31/h4-11,17,20,26,29H,12-13H2,1-3H3,(H,30,33)/t17-,20-,26-,28+/m1/s1
InChI Key HKSZLNNOFSGOKW-FYTWVXJKSA-N
References
1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011)
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]
2. Budworth J, Gescher A. (1995)
Differential inhibition of cytosolic and membrane-derived protein kinase C activity by staurosporine and other kinase inhibitors.
FEBS Lett., 362 (2): 139-42. [PMID:7536688]
3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011)
Comprehensive analysis of kinase inhibitor selectivity.
Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]
4. Djung JF, Mears RJ, Montalbetti CA, Coulter TS, Golebiowski A, Carr AN, Barker O, Greis KD, Zhou S, Dolan E et al.. (2011)
The synthesis and evaluation of indolylureas as PKCα inhibitors.
Bioorg. Med. Chem., 19 (8): 2742-50. [PMID:21435888]
5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013)
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.
Biochem. J., 451 (2): 313-28. [PMID:23398362]
6. Hall MD, Salam NK, Hellawell JL, Fales HM, Kensler CB, Ludwig JA, Szakács G, Hibbs DE, Gottesman MM. (2009)
Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.
J. Med. Chem., 52 (10): 3191-204. [PMID:19397322]
7. Ho KK, Parnell KM, Yuan Y, Xu Y, Kultgen SG, Hamblin S, Hendrickson TF, Luo B, Foulks JM, McCullar MV et al.. (2013)
Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors.
Bioorg. Med. Chem. Lett., 23 (2): 569-73. [PMID:23232060]
8. Lazareno S, Popham A, Birdsall NJ. (2000)
Allosteric interactions of staurosporine and other indolocarbazoles with N-[methyl-(3)H]scopolamine and acetylcholine at muscarinic receptor subtypes: identification of a second allosteric site.
Mol. Pharmacol., 58 (1): 194-207. [PMID:10860942]
9. Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchya H, Takahashi Y, Masuma R. (1977)
A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization.
J. Antibiot., 30 (4): 275-82. [PMID:863788]
10. Pandey A, Volkots DL, Seroogy JM, Rose JW, Yu JC, Lambing JL, Hutchaleelaha A, Hollenbach SJ, Abe K, Giese NA et al.. (2002)
Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.
J. Med. Chem., 45 (17): 3772-93. [PMID:12166950]
11. Qi ZH, Song M, Wallace MJ, Wang D, Newton PM, McMahon T, Chou WH, Zhang C, Shokat KM, Messing RO. (2007)
Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits.
J. Biol. Chem., 282 (45): 33052-63. [PMID:17875639]
12. Rüegg UT, Burgess GM. (1989)
Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases.
Trends Pharmacol. Sci., 10 (6): 218-20. [PMID:2672462]
13. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010)
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
Chem. Biol., 17 (11): 1241-9. [PMID:21095574]