Bisindolylmaleimide

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Bisindolylmaleimide
Bisindolylmaleimide I.svg
Identifiers
CAS number 133052-90-1
PubChem 2396
ChemSpider 2303
DrugBank DB03777
MeSH bisindolylmaleimide
Jmol-3D images Image 1
Properties
Molecular formula C25H24N4O2
Molar mass 412.484
Appearance orange solid
Density 1.3g/cm3
Melting point 208−210 °C
Boiling point 685.6 °C @ 760mmHg
Solubility in water soluble in DMSO
Hazards
Flash point 368.5 °C (695.3 °F; 641.6 K)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references
Het Group BI1
Identifiers
Symbol Het Group/Ligand: BI1
Pfam PF00069
SCOP 1uu8
SUPERFAMILY 1uu8
Proto-oncogene serine/threonine-protein kinase pim-1
Protein PIM1 PDB 1xqz.png
PDB rendering based on 1xqz.
Identifiers
Symbol PIM1
Entrez 5292
HUGO 8986
OMIM 164960
PDB 1YI3 (RCSB PDB PDBe PDBj)
RefSeq NM_002648
UniProt P11309
Other data
Locus Chr. 6 p21.2

BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.[1]

Function[edit]

The protein kinase C (PKC)[2] inhibitor Bis(indolyl)maleimide inhibitor BIM1[1] is clearly seen in the structure of PKCiota[3] (residue 574-turn[4] motif), need to be phosphorylated towards a PKCbeta-specific inhibitor site-directed mutagenesis of the compound for its full activation[5] and co-crystallized as an asymmetric pair which is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1)[6] are downstream characteristics of PKCs and PKB/AKT.[7]

Scope[edit]

The bound BIM1 inhibitor blocks bilobal[8] interactions, the ATP-binding site, features an ATP-competitive inhibitor, 2-methyl-1H-indol-3-yl-BIM-1,[8] the crystal structure[8] and catalytic subunit with a 20-amino acid substrate analog inhibitor structure is bilobal MgATP a transport protein that provide a more precise description of which is influenced by lobe-lobe interactions binding in cells expressing both forms a pair of kinase-inhibitor complexes[7] with ferritin in a soluble and non-toxic form (Poisson-Boltzmann[9]) and a portion of the inhibitor peptide[10] a lysine residue, has been shown to be involved in ATP binding.

Interactions[edit]

The PKCiota-BIM1 complex[4] interacts with the zinc finger of lambda/iota PKC characterization of lambda-interacting protein (LIP)[5] (lambda-interacting protein; a selective activator of lambda/iotaPKC). Phosphorylation of a PKC induces a conformation leading to import of a PKC into the nucleus.[11] The entire 587-amino acid coding region of a new PKC isoform, PKC iota.[11] Where Thr-412[5][12] (activation loop of the kinase domain) at PKCiota/lambda phosphorylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH)[13] that sort cargo to the anterograde pathway[14] the phosphorylation pathway(s) involved in this phenomenon[2] mimic glutamate and can adopt two limiting diastereomeric (syn and anti) conformation[15] biosynthetically related indolocarbazole analogs[16] and in Proto-oncogene serine/threonine-protein kinase Pim-1-Peptide as a phosphorylation target including itself. The bound BIM1 inhibitor blocks the ATP-binding site and puts the kinase domain into an intermediate open[7] conformation.[4] The value of such calculations lies in understanding[9] a variant was designed which showed improved binding characteristics[17] of configurationally stable atropisomeric bisindolylmaleimides[15] where the two kinase domains, and two different inhibitor conformers bind in different orientations,[7] the hinge region of staurosporine[18]-Pim-1 resembles[19] co-crystallized[8] as an asymmetric pair of biosynthetically 'related' indolocarbazole analogs.

References[edit]

  1. ^ a b Komander D, Kular GS, Schüttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM. (February 2004). "Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1". Structure. 12 (2): 215–26. doi:10.1016/S0969-2126(04)00007-3. PMID 14962382. 
  2. ^ a b Cartee L, Smith R, Dai Y, Rahmani M, Rosato R, Almenara J, Dent P, Grant S. (June 2002). "Synergistic induction of apoptosis in human myeloid leukemia cells by phorbol 12-myristate 13-acetate and flavopiridol proceeds via activation of both the intrinsic and tumor necrosis factor-mediated extrinsic cell death pathways". Mol Pharmacol. 61 (6): 1313–21. doi:10.1124/mol.61.6.1313. PMID 12021392. 
  3. ^ Baldwin RM, Parolin DA, Lorimer IA. (June 2008). "Regulation of glioblastoma cell invasion by PKC iota and RhoB". Oncogene. 27 (25): 3587–95. doi:10.1038/sj.onc.1211027. PMID 18212741. 
  4. ^ a b c Messerschmidt A, Macieira S, Velarde M, Bädeker M, Benda C, Jestel A, Brandstetter H, Neuefeind T, Blaesse M. (September 2005). "Crystal structure of the catalytic domain of human atypical protein kinase C-iota reveals interaction mode of phosphorylation site in turn motif". J Mol Biol. 352 (4): 918–31. doi:10.1016/j.jmb.2005.07.060. PMID 16125198. 
  5. ^ a b c Diaz-Meco MT, Municio MM, Sanchez P, Lozano J, Moscat J. (January 1996). "Lambda-interacting protein, a novel protein that specifically interacts with the zinc finger domain of the atypical protein kinase C isotype lambda/iota and stimulates its kinase activity in vitro and in vivo". Mol Cell Biol. 16 (1): 105–14. PMC 230983. PMID 8524286. 
  6. ^ Peifer C, Alessi DR. (December 2008). "Small-molecule inhibitors of PDK1". ChemMedChem. 3 (12): 1810–38. doi:10.1002/cmdc.200800195. PMID 18972468. 
  7. ^ a b c d Gassel M, Breitenlechner CB, König N, Huber R, Engh RA, Bossemeyer D. (May 2004). "The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A". J Biol Chem. 279 (22): 23679–90. doi:10.1074/jbc.M314082200. PMID 14996846. 
  8. ^ a b c d Grodsky Grodsky N, Li Y, Bouzida D, Love R, Jensen J, Nodes B, Nonomiya J, Grant S. (November 2006). "Structure of the catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor". Biochemistry. 45 (47): 13970–81. doi:10.1021/bi061128h. PMID 17115692. 
  9. ^ a b Page CS, Bates PA. (December 2006). "Can MM-PBSA calculations predict the specificities of protein kinase inhibitors?". J Comput Chem. 27 (16): 1990–2007. doi:10.1002/jcc.20534. PMID 17036304. 
  10. ^ Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM. (July 1991). "Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase". Science. 253 (5018): 407–14. Bibcode:1991Sci...253..407K. doi:10.1126/science.1862342. PMID 1862342. 
  11. ^ a b White WO, Seibenhener ML, Wooten MW. (January 2002). "Phosphorylation of tyrosine 256 facilitates nuclear import of atypical protein kinase C". J Cell Biochem. 85 (1): 42–53. doi:10.1002/jcb.10101. PMID 11891849. 
  12. ^ Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd. (March 2008). "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis". J Proteome Res. 7 (3): 1346–51. doi:10.1021/pr0705441. PMID 18220336. 
  13. ^ Tisdale EJ. (December 2003). "Rab2 interacts directly with atypical protein kinase C (aPKC) iota/lambda and inhibits aPKCiota/lambda-dependent glyceraldehyde-3-phosphate dehydrogenase phosphorylation". J Biol Chem. 278 (52): 52424–30. doi:10.1074/jbc.M309343200. PMID 14570876. 
  14. ^ Tisdale EJ, Artalejo CR. (March 2006). "Src-dependent aprotein kinase C iota/lambda (aPKCiota/lambda) tyrosine phosphorylation is required for aPKCiota/lambda association with Rab2 and glyceraldehyde-3-phosphate dehydrogenase on pre-golgi intermediates". J Biol Chem. 281 (13): 8436–42. doi:10.1074/jbc.M513031200. PMID 16452474. 
  15. ^ a b Barrett S, Bartlett S, Bolt A, Ironmonger A, Joce C, Nelson A, Woodhall T. (October 2005). "Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides". Chemistry. 11 (21): 6277–85. doi:10.1002/chem.200500520. PMID 16075446. 
  16. ^ Sánchez C, Méndez C, Salas JA. (December 2006). "Indolocarbazole natural products: occurrence, biosynthesis, and biological activity". Nat Prod Rep. 23 (6): 1007–45. doi:10.1039/B601930G. PMID 17119643. 
  17. ^ Bandeiras TM, Hillig RC, Matias PM, Eberspaecher U, Fanghänel J, Thomaz M, Miranda S, Crusius K, Pütter V, Amstutz P, Gulotti-Georgieva M, Binz HK, Holz C, Schmitz AA, Lang C, Donner P, Egner U, Carrondo MA, Müller-Tiemann B. (April 2008). "Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin". Acta Crystallogr D 64 (4): 339–53. doi:10.1107/S0907444907068217. PMID 18391401. 
  18. ^ Lee SK, Stern PH. (October 2000). "Divergent effects of protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide I (GF109203X) on bone resorption". Biochem Pharmacol. 60 (7): 923–6. doi:10.1016/S0006-2952(00)00418-4. PMID 10974200. 
  19. ^ M.D.Jacobs,J.Black,O.Futer,L.Swenson,B.Hare,M.Fleming, K.Saxena (May 2005). "Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002". J Biol Chem 280 (14): 13728–13734. doi:10.1074/jbc.M413155200. PMID 15657054.