BIM-1

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Contents

BIM-1
Bis(indolyl)maleimide.svg
Names
IUPAC name
3-{1-[3-(Dimethylamino)propyl]-1H-indol-3-yl}-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
Other names
RBT205 INHIBITOR, BI1
Identifiers
3D model (JSmol)
ChemSpider
DrugBank
ECHA InfoCard 100.122.321 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 603-702-0
MeSH bisindolylmaleimide
PubChem CID
UNII
  • Key: QMGUOJYZJKLOLH-UHFFFAOYSA-N
  • InChI=1S/C25H24N4O2/c1-28(2)12-7-13-29-15-19(17-9-4-6-11-21(17)29)23-22(24(30)27-25(23)31)18-14-26-20-10-5-3-8-16(18)20/h3-6,8-11,14-15,26H,7,12-13H2,1-2H3,(H,27,30,31)
  • O=C5C(\c2c1ccccc1[nH]c2)=C(\c4c3ccccc3n(c4)CCCN(C)C)C(=O)N5
Properties
C25H24N4O2
Molar mass 412.493 g·mol−1
AppearanceOrange solid
Density 1.3 g/cm3
Melting point 208 to 210 °C (406 to 410 °F; 481 to 483 K)
Solubility in DMSO Soluble[ vague ]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

BIM-1 (GF 109203X) and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) 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] [2]

Function

BIM-1 is present in the structure of PKCiota [3] (residue 574-turn [4] motif). It needs 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

The bound BIM-1 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

The PKCiota-BIM-1 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/iota PKC). 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 BIM-1 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. It is a modulator of the 5-HT2A receptor. [20]

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

<span class="mw-page-title-main">Pyruvate dehydrogenase lipoamide kinase isozyme 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).

c-Raf Mammalian protein found in Homo sapiens

RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.

<span class="mw-page-title-main">Serine/threonine-specific protein kinase</span> Class of protein kinase enzymes

A serine/threonine protein kinase is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protein kinases are serine/threonine kinases (STK).

The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C (PKC) isoforms. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.

<span class="mw-page-title-main">Protein kinase C zeta type</span>

Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the PRKCZ gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ is thought to be responsible for maintaining long-term memories in the brain. The importance of PKCζ in the creation and maintenance of long-term potentiation was first described by Todd Sacktor and his colleagues at the SUNY Downstate Medical Center in 1993.

<span class="mw-page-title-main">Cyclin-dependent kinase 1</span> Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in the species Homo sapiens

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">PRKCQ</span> Protein-coding gene in the species Homo sapiens

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.

<span class="mw-page-title-main">Histidine kinase</span> Family of enzymes important in cell signaling

Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are homodimers that exhibit autokinase, phosphotransfer, and phosphatase activity. HKs can act as cellular receptors for signaling molecules in a way analogous to tyrosine kinase receptors (RTK). Multifunctional receptor molecules such as HKs and RTKs typically have portions on the outside of the cell that bind to hormone- or growth factor-like molecules, portions that span the cell membrane, and portions within the cell that contain the enzymatic activity. In addition to kinase activity, the intracellular domains typically have regions that bind to a secondary effector molecule or complex of molecules that further propagate signal transduction within the cell. Distinct from other classes of protein kinases, HKs are usually parts of a two-component signal transduction mechanisms in which HK transfers a phosphate group from ATP to a histidine residue within the kinase, and then to an aspartate residue on the receiver domain of a response regulator protein. More recently, the widespread existence of protein histidine phosphorylation distinct from that of two-component histidine kinases has been recognised in human cells. In marked contrast to Ser, Thr and Tyr phosphorylation, the analysis of phosphorylated Histidine using standard biochemical and mass spectrometric approaches is much more challenging, and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation on proteins isolated from human cells.

<span class="mw-page-title-main">PRKCI</span> Protein-coding gene in the species Homo sapiens

Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.

<span class="mw-page-title-main">Protein kinase N1</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase N1 is an enzyme that in humans is encoded by the PKN1 gene.

<span class="mw-page-title-main">Protein kinase, AMP-activated, alpha 1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the PRKAA1 gene.

<span class="mw-page-title-main">PKN2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase N2 is an enzyme that in humans and Strongylocentrotus purpuratus is encoded by the PKN2 gene.

<span class="mw-page-title-main">PKIA</span> Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase inhibitor alpha is a protein that in humans is encoded by the PKIA gene.

<span class="mw-page-title-main">Phosphoinositide-dependent kinase-1</span> Protein-coding gene in the species Homo sapiens

In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the PDPK1 gene in humans. It is implicated in the development and progression of melanomas.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

<span class="mw-page-title-main">Balanol</span> Fungal metabolite

Balanol is a fungal metabolite produced by the fungus Verticillium balanoides. It is a potent inhibitor of the serine/threonine kinases protein kinase A (PKA) and protein kinase C (PKC), binding in a similar manner with that of ATP. Balanol was discovered in 1993 in the search for novel inhibitors of PKC, a member of a family of serine/threonine kinases whose overactivation is associated with numerous human diseases of signal transduction including cancer. However, much of the research on balanol focuses on how chemical modifications of the molecular structure affect binding to PKA. Indeed, balanol, its chemically altered analogs, and their interactions with PKA in particular are used to illuminate the roles of selectivity and protein flexibility in the inhibition of kinases. For instance, the X-ray crystal structure of balanol in complex with PKA was used in order to confer selectivity and to improve pharmacological efficacy of inhibitors of the H. sapiens Akt (PKB), another serine/threonine protein kinase implicated in the proper functioning of many cellular processes.

References

  1. ↑ 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/j.str.2004.01.005 . PMID   14962382.
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  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.
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  11. 1 2 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. S2CID   221311830.
  12. ↑ Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR (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 . PMC   3742308 . PMID   16452474.
  15. 1 2 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: A European Journal. 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.
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