|
|
| Line 1: |
Line 1: |
| - | {{STRUCTURE_4n6y| PDB=4n6y | SCENE= }}
| + | ==Pim1 Complexed with a phenylcarboxamide== |
| - | ===Pim1 Complexed with a phenylcarboxamide=== | + | <StructureSection load='4n6y' size='340' side='right' caption='[[4n6y]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[4n6y]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N6Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N6Y FirstGlance]. <br> |
| | + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2HV:2-(ACETYLAMINO)-N-[2-(PIPERIDIN-1-YL)PHENYL]-1,3-THIAZOLE-4-CARBOXAMIDE'>2HV</scene><br> |
| | + | <tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| | + | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4n6z|4n6z]], [[4n70|4n70]]</td></tr> |
| | + | <tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| | + | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> |
| | + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4n6y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n6y OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4n6y RCSB], [http://www.ebi.ac.uk/pdbsum/4n6y PDBsum]</span></td></tr> |
| | + | <table> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described. |
| | | | |
| - | ==Function==
| + | Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.,Burger MT, Han W, Lan J, Nishiguchi G, Bellamacina C, Lindval M, Atallah G, Ding Y, Mathur M, McBride C, Beans EL, Muller K, Tamez V, Zhang Y, Huh K, Feucht P, Zavorotinskaya T, Dai Y, Holash J, Castillo J, Langowski J, Wang Y, Chen MY, Garcia PD ACS Med Chem Lett. 2013 Oct 15;4(12):1193-7. doi: 10.1021/ml400307j. eCollection , 2013 Dec 12. PMID:24900629<ref>PMID:24900629</ref> |
| - | [[http://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN]] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[4n6y]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4N6Y OCA].
| + | </div> |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | <references group="xtra"/><references/> | + | __TOC__ |
| - | [[Category: Homo sapiens]] | + | </StructureSection> |
| | + | [[Category: Human]] |
| | [[Category: Non-specific serine/threonine protein kinase]] | | [[Category: Non-specific serine/threonine protein kinase]] |
| | [[Category: Bellamacina, C R.]] | | [[Category: Bellamacina, C R.]] |
| Structural highlights
4n6y is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | NonStd Res: | |
| Related: | 4n6z, 4n70 |
| Gene: | PIM1 (HUMAN) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Publication Abstract from PubMed
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.,Burger MT, Han W, Lan J, Nishiguchi G, Bellamacina C, Lindval M, Atallah G, Ding Y, Mathur M, McBride C, Beans EL, Muller K, Tamez V, Zhang Y, Huh K, Feucht P, Zavorotinskaya T, Dai Y, Holash J, Castillo J, Langowski J, Wang Y, Chen MY, Garcia PD ACS Med Chem Lett. 2013 Oct 15;4(12):1193-7. doi: 10.1021/ml400307j. eCollection , 2013 Dec 12. PMID:24900629[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Burger MT, Han W, Lan J, Nishiguchi G, Bellamacina C, Lindval M, Atallah G, Ding Y, Mathur M, McBride C, Beans EL, Muller K, Tamez V, Zhang Y, Huh K, Feucht P, Zavorotinskaya T, Dai Y, Holash J, Castillo J, Langowski J, Wang Y, Chen MY, Garcia PD. Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors. ACS Med Chem Lett. 2013 Oct 15;4(12):1193-7. doi: 10.1021/ml400307j. eCollection , 2013 Dec 12. PMID:24900629 doi:http://dx.doi.org/10.1021/ml400307j
|
