Target Information
Target General Infomation | |||||
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Target ID |
T50594
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Former ID |
TTDNC00498
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Target Name |
Proto-oncogene pim-1
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Gene Name |
PIM1
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Synonyms |
Serine/threonine-protein kinase pim-1; PIM1
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Target Type |
Clinical Trial
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Disease | Cancer [ICD9: 140-229; ICD10: C00-C96] | ||||
Function |
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.
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BioChemical Class |
Kinase
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MPHEPHEPLTPPFSALPDPAGAPSRRQSRQRPQLSSDSPSAFRASRSHSRNATRSHSHSH
SPRHSLRHSPGSGSCGSSSGHRPCADILEVGMLLSKINSLAHLRAAPCNDLHATKLAPGK EKEPLESQYQVGPLLGSGGFGSVYSGIRVSDNLPVAIKHVEKDRISDWGELPNGTRVPME VVLLKKVSSGFSGVIRLLDWFERPDSFVLILERPEPVQDLFDFITERGALQEELARSFFW QVLEAVRHCHNCGVLHRDIKDENILIDLNRGELKLIDFGSGALLKDTVYTDFDGTRVYSP PEWIRYHRYHGRSAAVWSLGILLYDMVCGDIPFEHDEEIIRGQVFFRQRVSSECQHLIRW CLALRPSDRPTFEEIQNHPWMQDVLLPQETAEIHLHSLSPGPSK |
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Drugs and Mode of Action | |||||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Jak-STAT signaling pathway | ||||
MicroRNAs in cancer | |||||
Acute myeloid leukemia | |||||
NetPath Pathway | IL9 Signaling Pathway | ||||
IL5 Signaling Pathway | |||||
IL2 Signaling Pathway | |||||
TGF_beta_Receptor Signaling Pathway | |||||
TCR Signaling Pathway | |||||
Pathway Interaction Database | GMCSF-mediated signaling events | ||||
Validated targets of C-MYC transcriptional activation | |||||
Role of Calcineurin-dependent NFAT signaling in lymphocytes | |||||
IL5-mediated signaling events | |||||
IL3-mediated signaling events | |||||
C-MYB transcription factor network | |||||
WikiPathways | Ectoderm Differentiation | ||||
Hematopoietic Stem Cell Differentiation | |||||
References | |||||
Ref 531493 | Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem. 2011 Jun 23;54(12):4172-86. | ||||
Ref 531649 | 7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity. Bioorg Med Chem Lett. 2011 Nov 15;21(22):6687-92. | ||||
Ref 531724 | 7,8-dichloro-1-oxo-beta-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes. J Med Chem. 2012 Jan 12;55(1):403-13. | ||||
Ref 531895 | Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31. |
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