生物活性

• 描述The immunophilin FKBP12 is one of the most abundant and conserved proteins in biology. It is the primary receptor for the immunosuppressant actions of ascomycin in whose presence FKBP12 binds to and inhibits CaN, disrupting IL formation in lymphocytes. Tacrolimus Monohydrate is the monohydrate form of Tacrolimus. Tacrolimus(FK-506) block early events in T lymphocyte activation by its immunosuppressive effects such as phosphoinositide turnover, reducing peptidyl-prolyl isomerase activity in T cells by binding to the FKBP12 which will create a new complex. FK-506 inhibited FKBP12 for activity with IC50 of 3nM. Furthermore, FK-506 Inhibited secretion of IL-1, IL-2 (IC50 = 1 nM), IL-3, IL-4, IL-6 (IC50 = 35 nM), GM-CSF, TNFα (IC50 = 10 nM), IFNγ and Myc from activated T cells. In terms of anti-inflammatory activity in rat RBL2H3 cells, the inhibition of FK506 to DNP-BSA-induced TNF-alpha production pre-incubated for 15 mins with IC50 of 0.25 nM. FK-506 can decrease the serum nitrate and thiobarbituric acid reactive substance (TBARS) levels along with reduction in tissue myeloperoxidase (MPO) and total calcium levels. FK-506 ameliorates the increase in the neuronal edema and axonal degeneration in rats with ischemia reperfusion (I/R) . In the presence of 10ng/mL FK-506, nuclear extracts from Jurkat cells that had been stimulated for 2 hours with PMA and ionomycin transcribe the IL-2 G-less template in amounts nearly equivalent to extracts from fully stimulated Jurkat cells . Overexpression of FKBP12 by transfection enhanced the ability of FK-506 to inhibit calcineurin phosphatase activity with IC50 of 2nM, compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK-506 inhibition of IgE activation-induced transcripts for TNF-α decreased from 40nM to 10nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM to 35 nM, suggesting FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-α and IL-6 transcripts.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01028716	Acute Biphenotypic Leukemia ... more >> Acute Erythroid Leukemia in Remission Acute Leukemia in Remission Acute Megakaryoblastic Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Acute Myeloid Leukemia in Remission Acute Myeloid Leukemia With FLT3/ITD Mutation Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM Acute Myeloid Leukemia With Multilineage Dysplasia Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214 Acute Undifferentiated Leukemia Adult Acute Lymphoblastic Leukemia in Complete Remission B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1) B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Burkitt Lymphoma Childhood Acute Lymphoblastic Leukemia in Complete Remission DS Stage II Plasma Cell Myeloma DS Stage III Plasma Cell Myeloma Myelodysplastic Syndrome Recurrent Anaplastic Large Cell Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Follicular Lymphoma Recurrent Hodgkin Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Secondary Acute Myeloid Leukemia T Lymphoblastic Lymphoma Collapse <<	Phase 2	Recruiting	-	United States, Washington ... more >> VA Puget Sound Health Care System Not yet recruiting Seattle, Washington, United States, 98101 Contact: Thomas Chauncey    206-764-2969    thomas.chauncey@va.gov    Principal Investigator: Thomas Chauncey          Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Rachel B. Salit    206-667-1317    rsalit@fredhutch.org    Principal Investigator: Rachel B. Salit Collapse <<
  NCT03602898	Acute Lymphoblastic Leukemia i... more >>n Remission Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Acute Myeloid Leukemia in Remission Blasts 5 Percent or Less of Bone Marrow Nucleated Cells Chronic Myelomonocytic Leukemia Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Donor Minimal Residual Disease Myelodysplastic Syndrome Myelofibrosis Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Recurrent Hodgkin Lymphoma Recurrent Non-Hodgkin Lymphoma Refractory Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Collapse <<	Phase 2	Not yet recruiting	September 17, 2023	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Not yet recruiting Seattle, Washington, United States, 98109 Contact: Masumi Ueda    206-667-4546       Principal Investigator: Masumi Ueda Collapse <<
  NCT00589316	Acute Myeloid Leukemia Arising... more >> From Previous Myelodysplastic Syndrome Adult Acute Lymphoblastic Leukemia in Remission Adult Acute Myeloid Leukemia in Remission CD45-Positive Neoplastic Cells Present Chronic Myelomonocytic Leukemia Previously Treated Myelodysplastic Syndrome Refractory Anemia With Excess Blasts Refractory Anemia With Ring Sideroblasts Refractory Cytopenia With Multilineage Dysplasia Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts Collapse <<	Phase 1	Active, not recruiting	October 1, 2024	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Seattle, Washington, United States, 98109 Collapse <<

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• 参考文献

• [1] Vogel KR, Ainslie GR, et al. mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis. 2016 Nov;39(6):877-886.

  [2] Thomson AW, Bonham CA, et al. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91.