Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT69J2Z)

• DTT Name: Serine/threonine-protein kinase pim-2 (PIM2)
• Synonyms: Pim-2h; PIM2
• Gene Name: PIM2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: PIM2_HUMAN
• TTD ID: T07279
• EC Number: EC 2.7.11.1
• Sequence:
  MLTKPLQGPPAPPGTPTPPPGGKDREAFEAEYRLGPLLGKGGFGTVFAGHRLTDRLQVAI
  KVIPRNRVLGWSPLSDSVTCPLEVALLWKVGAGGGHPGVIRLLDWFETQEGFMLVLERPL
  PAQDLFDYITEKGPLGEGPSRCFFGQVVAAIQHCHSRGVVHRDIKDENILIDLRRGCAKL
  IDFGSGALLHDEPYTDFDGTRVYSPPEWISRHQYHALPATVWSLGILLYDMVCGDIPFER
  DQEILEAELHFPAHVSPDCCALIRRCLAPKPSSRPSLEEILLDPWMQTPAEDVPLNPSKG
  GPAPLAWSLLP
• Function: Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti- apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.
• KEGG Pathway: Acute myeloid leukemia (hsa05221)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LGH-447	DMQN9ME	Multiple myeloma	2A83	Phase 1/2	[1]
AZD1208	DMBEA6V	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IDDBCP226234	DMBFX5H	Inflammation	1A00-CA43.1	Investigative	[3]
PMID21982499C14k	DM0VOXN	Discovery agent	N.A.	Investigative	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Multiple myeloma	2C82	Bone marrow	6.70E-03	0.59	1.1

References

• [1] Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014 Apr 1;20(7):1834-45.
• [2] AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014 Feb 6;123(6):905-13.
• [3] 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: 2159).
• [4] 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.