Target Information
Target General Information | Top | |||||
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Target ID |
T74073
(Former ID: TTDI01794)
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Target Name |
Serine/threonine-protein kinase pim (PIM)
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Gene Name |
NO-GeName
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
3 | Myeloproliferative neoplasm [ICD-11: 2A20] | |||||
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 throughphosphorylation 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 proteinstability. 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. Actsalso 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 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | INCB53914 | Drug Info | Phase 1/2 | Advanced malignancy | [1] | |
2 | SEL24 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [2] | |
3 | PIM447 | Drug Info | Phase 1 | Myelofibrosis | [1] | |
4 | TP-3654 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | INCB53914 | Drug Info | [1] | |||
2 | SEL24 | Drug Info | [4] | |||
3 | PIM447 | Drug Info | [1] | |||
4 | TP-3654 | Drug Info | [5] |
Chemical Structure based Activity Landscape of Target | Top |
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Co-Targets | Top | |||||
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Co-Targets |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | ClinicalTrials.gov (NCT03008187) SEL24/MEN1703 in Patients With Acute Myeloid Leukemia. U.S. National Institutes of Health. | |||||
REF 3 | ClinicalTrials.gov (NCT03715504) Study of TP-3654 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 4 | A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia. Oncotarget. 2018 Mar 30;9(24):16917-16931. | |||||
REF 5 | Clinical pipeline report, company report or official report of Sumitomo Dainippon Pharma. |
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