General Information of Drug Therapeutic Target (DTT) (ID: TTTN5QW)

DTT Name Serine/threonine-protein kinase pim-1 (PIM1)
Synonyms Pim-1 proto-oncogene, serine/threonine kinase; PIM
Gene Name PIM1
DTT Type
Clinical trial target
[1]
BioChemical Class
Kinase
UniProt ID
PIM1_HUMAN
TTD ID
T50594
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.7.11.1
Sequence
MLLSKINSLAHLRAAPCNDLHATKLAPGKEKEPLESQYQVGPLLGSGGFGSVYSGIRVSD
NLPVAIKHVEKDRISDWGELPNGTRVPMEVVLLKKVSSGFSGVIRLLDWFERPDSFVLIL
ERPEPVQDLFDFITERGALQEELARSFFWQVLEAVRHCHNCGVLHRDIKDENILIDLNRG
ELKLIDFGSGALLKDTVYTDFDGTRVYSPPEWIRYHRYHGRSAAVWSLGILLYDMVCGDI
PFEHDEEIIRGQVFFRQRVSSECQHLIRWCLALRPSDRPTFEEIQNHPWMQDVLLPQETA
EIHLHSLSPGPSK
Function
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. Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis.
KEGG Pathway
Jak-STAT signaling pathway (hsa04630 )
MicroRNAs in cancer (hsa05206 )
Acute myeloid leukemia (hsa05221 )
Reactome Pathway
STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518 )
Signaling by FLT3 fusion proteins (R-HSA-9703465 )
Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
2 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
SEL-24 DMH064K Acute myeloid leukaemia 2A60 Phase 1/2 [1]
CXR-1002 DM4GJ50 Solid tumour/cancer 2A00-2F9Z Phase 1 [2]
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1 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Benzothiazine derivative 1 DMMVHY4 N. A. N. A. Patented [3]
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5 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
leucettine L41 DMBYND6 Discovery agent N.A. Investigative [4]
NCGC00167772-01 DMY8RT9 Discovery agent N.A. Investigative [1]
PMID21982499C14k DM0VOXN Discovery agent N.A. Investigative [5]
PMID22136433C20 DMI8217 Discovery agent N.A. Investigative [6]
SMI-4a DMBLWMS Non-small-cell lung cancer 2C25 Investigative [7]
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Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Multiple myeloma 2C82 Bone marrow 4.83E-01 0.06 0.2
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References

1 URL: 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).
2 123 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.
3 Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
4 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.
5 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.
6 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.
7 Pim-1 inhibitor SMI-4a suppresses tumor growth in non-small cell lung cancer via PI3K/AKT/mTOR pathway. Onco Targets Ther. 2019 Apr 23;12:3043-3050.