Target General Infomation
Target ID
T50594
Former ID
TTDNC00498
Target Name
Proto-oncogene pim-1
Gene Name
PIM1
Synonyms
Serine/threonine-protein kinase pim-1; PIM1
Target Type
Clinical Trial
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.
BioChemical Class
Kinase
UniProt ID
EC Number
EC 2.7.11.1
Sequence
MPHEPHEPLTPPFSALPDPAGAPSRRQSRQRPQLSSDSPSAFRASRSHSRNATRSHSHSH
SPRHSLRHSPGSGSCGSSSGHRPCADILEVGMLLSKINSLAHLRAAPCNDLHATKLAPGK
EKEPLESQYQVGPLLGSGGFGSVYSGIRVSDNLPVAIKHVEKDRISDWGELPNGTRVPME
VVLLKKVSSGFSGVIRLLDWFERPDSFVLILERPEPVQDLFDFITERGALQEELARSFFW
QVLEAVRHCHNCGVLHRDIKDENILIDLNRGELKLIDFGSGALLKDTVYTDFDGTRVYSP
PEWIRYHRYHGRSAAVWSLGILLYDMVCGDIPFEHDEEIIRGQVFFRQRVSSECQHLIRW
CLALRPSDRPTFEEIQNHPWMQDVLLPQETAEIHLHSLSPGPSK
Drugs and Mode of Action
Drug(s) CXR-1002 Drug Info Phase 1 Cancer [549291]
Inhibitor compound 14k Drug Info [531649]
compound 2 Drug Info [531895]
compound 20 Drug Info [531724]
CXR-1002 Drug Info [551578]
leucettine L41 Drug Info [531493]
NCGC00167772-01 Drug Info [543563]
Pim1 inhibitors Drug Info [543563]
SEL-24 Drug Info [543563]
Small molecule 18a Drug Info [543563]
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 549291Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034732)
Ref 531493Leucettines, 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 5316497-(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 5317247,8-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 531895Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31.
Ref 543563(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2158).
Ref 551578123 Antitumor activity of CXR1002, a novel anti-cancer clinical phase compound that induces ER stress and inhibits PIM kinases: Human tumor xenograft efficacy and in vitro mode of action. EJC Supplements, 2010; 8(7):45-46.

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