Target Information
| Target General Information | Top | |||||
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| Target ID |
T07279
(Former ID: TTDNR00746)
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| Target Name |
Serine/threonine-protein kinase pim-2 (PIM2)
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| Synonyms |
Pim-2h; PIM2
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| Gene Name |
PIM2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Multiple myeloma [ICD-11: 2A83] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 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.
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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 |
MLTKPLQGPPAPPGTPTPPPGGKDREAFEAEYRLGPLLGKGGFGTVFAGHRLTDRLQVAI
KVIPRNRVLGWSPLSDSVTCPLEVALLWKVGAGGGHPGVIRLLDWFETQEGFMLVLERPL PAQDLFDYITEKGPLGEGPSRCFFGQVVAAIQHCHSRGVVHRDIKDENILIDLRRGCAKL IDFGSGALLHDEPYTDFDGTRVYSPPEWISRHQYHALPATVWSLGILLYDMVCGDIPFER DQEILEAELHFPAHVSPDCCALIRRCLAPKPSSRPSLEEILLDPWMQTPAEDVPLNPSKG GPAPLAWSLLP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | LGH-447 | Drug Info | Phase 1/2 | Multiple myeloma | [2] | |
| 2 | AZD1208 | Drug Info | Phase 1 | Solid tumour/cancer | [3], [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | LGH-447 | Drug Info | [1] | |||
| 2 | AZD1208 | Drug Info | [4], [5] | |||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | IDDBCP226234 | Drug Info | [6] | |||
| 2 | PMID21982499C14k | Drug Info | [7] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 2-(2,6-Difluorophenyl)-N-{4-[(3s)-Pyrrolidin-3-Yloxy]pyridin-3-Yl}-1,3-Thiazole-4-Carboxamide | Ligand Info | |||||
| Structure Description | PIM2 kinase in complex with Compound 1s | PDB:4X7Q | ||||
| Method | X-ray diffraction | Resolution | 2.33 Å | Mutation | No | [8] |
| PDB Sequence |
AFEAEYRLGP
36 LLGKGFGTVF47 AGHRLTDRLQ57 VAIKVIPRCP81 LEVALLWKVG91 AGGGHPGVIR 101 LLDWFETFML114 VLERPLPAQD124 LFDYITEKGP134 LGEGPSRCFF144 GQVVAAIQHC 154 HSRGVVHRDI164 KDENILIDLR174 RGCAKLIDFG184 SGALLHDEPY194 TDFDGTRVYS 204 PPEWISRHQY214 HALPATVWSL224 GILLYDMVCG234 DIPFERDQEI244 LEAELHFPAH 254 VSPDCCALIR264 RCLAPKPSSR274 PSLEEILLDP284 WMQ
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| Ligand Name: Ruthenium-pyridocarbazole-1 | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF THE HUMAN PIM2 IN COMPLEX WITH A RUTHENIUM ORGANOMETALLIC LIGAND RU1 | PDB:2IWI | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [9] |
| PDB Sequence |
YRLGPLLGKG
41 GFGTVFAGHR51 LTDRLQVAIK61 VIPRNRVLVT79 CPLEVALLWK89 VGAGGGHPGV 99 IRLLDWFFML114 VLERPLPAQD124 LFDYITEKGP134 LGEGPSRCFF144 GQVVAAIQHC 154 HSRGVVHRDI164 KDENILIDLR174 RGCAKLIDFG184 SGALLHDEPY194 TDFDGTRVYS 204 PPEWISRHQY214 HALPATVWSL224 GILLYDMVCG234 DIPFERDQEI244 LEAELHFPAH 254 VSPDCCALIR264 RCLAPKPSSR274 PSLEEILLDP284 WMQT
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Similarity Proteins
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Acute myeloid leukemia | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | IL1 Signaling Pathway | |||||
| 2 | TCR Signaling Pathway | |||||
| 3 | IL2 Signaling Pathway | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Hematopoietic Stem Cell Differentiation | |||||
| References | Top | |||||
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| REF 1 | Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014 Apr 1;20(7):1834-45. | |||||
| REF 2 | ClinicalTrials.gov (NCT02144038) Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients With Relapsed and Refractory Multiple Myeloma. U.S. National Institutes of Health. | |||||
| REF 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. (Ligand id: 7698). | |||||
| REF 4 | 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. | |||||
| REF 5 | PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer. J Natl Cancer Inst. 2014 Dec 13;107(2). pii: dju407. | |||||
| REF 6 | 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). | |||||
| REF 7 | 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 8 | Structure-based design of low-nanomolar PIM kinase inhibitors. Bioorg Med Chem Lett. 2015 Feb 1;25(3):474-80. | |||||
| REF 9 | Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor. PLoS One. 2009 Oct 20;4(10):e7112. | |||||
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