生物活性

• 靶点	HDAC IC50:27nM

• 描述HDACs (Histone deacetylases) are a group of enzymes that remove acetyl groups and regulate the histone tail, protein-DNA interaction, chromatin conformation, and even transcription. There are 18 mammalian HDACs divided into four classes: class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), class III (sirtuin family: sirt1-sirt7) and class IV (HDAC11)^[1]. Belinostat, also called as PXD101, is a pan-HDAC inhibitor (IC50 = 27 nM, measured by HDAC enzymatic activity)^[2], inhibiting class I, II and IV HDAC isoforms with nanomolar potency^[3]. Like other HDAC pan inhibitors, the hyperacetylation of H3 and H4, which are the biomarkers for the inhibition of class I HDAC, can be observed in A2780 cells treated with 1 μM belinostat for various times (0.5 - 36h). Belinostat can inhibit the growth of a number of human tumor cell lines from various origins, including A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852 cells, with IC50 ranging 0.2 - 3.4 μM. The induction of P21 and apoptosis, as determined with measurement of PARP cleavage, by belinostat can be observed after drug incubation for 24h with concentration <1 μM in these cell lines, except for PC3 and 2780AD cell line. Belinostat shows good pharmacokinetic and pharmacodynamic properties. Treatment of belinostat 10 - 40 mg/kg daily for a week can inhibit the tumor growth of A2780 tumor-bearing mice in a dose-dependent manner, along with the increase of acetylated histone H4^[2]. Co-administration of belinostat with bortezomib can synergistically induce cell death in CLL cells, which may due to the involving of other mechanism, like NF-kB inactivation and perturbation in the expression of proapoptotic and antiapoptotic proteins^[4]. Belinostat was approved for the treatment of patients with relapsed or refractory PTCL. Its clinical trial of treatment for solid tumors/hematological malignancies is undergoing^[5].
• 作用机制The hydroxamic structure of belinostat can chelate the Zn ion of HDACs^[6].

• 动物研究
  剂量	Mice (i.p.): min = 20 mg/kg[7], max = 100 mg/kg[8]
  给药途径	i.p.
  动物药代数据	Animal Monkeys[9] Dose 10 mg/kg Administration IV infusion T1/2 0.47 h AUC0→∞ 13000 ng·h/ml CL 258 ml/min/m2 Vdss 0.20 L/kg MRT 0.26 h

• 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
  NCT03432741	Breast Adenocarcinoma ... more >> Recurrent Breast Carcinoma Recurrent Hodgkin Lymphoma Recurrent Mycosis Fungoides Recurrent Non-Hodgkin Lymphoma Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma Refractory Hodgkin Lymphoma Refractory Mycosis Fungoides Refractory Nodal Marginal Zone Lymphoma Refractory Non-Hodgkin Lymphoma Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma Stage IV Breast Cancer AJCC v6 and v7 Collapse <<	Phase 1	Recruiting	May 1, 2019	United States, Minnesota ... more >> Mayo Clinic Recruiting Rochester, Minnesota, United States, 55905 Contact: Clinical Trials Referral Office    855-776-0015       Principal Investigator: Grzegorz S. Nowakowski Collapse <<
  NCT00131261	Multiple Myeloma	Phase 2	Completed	-	United States, California ... more >> James Berenson, MD, Inc West Hollywood, California, United States, 90069 United States, Florida H. Lee Moffitt Cancer Center Tampa, Florida, United States, 33612 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 United States, New York Research Facility New York, New York, United States, 10021 Denmark Rigshospitalet Copenhagen, Denmark, 2100 Norway Research Facility Bergen, Norway, N-5021 Research Facility Oslo, Norway, N-0407 Research Facility Trondheim, Norway, N-7006 United Kingdom Christie Hospital NHS Trust Manchester, United Kingdom, M20 4BX The Royal Marsden NHS Trust Surrey, United Kingdom, SM2 5NG Collapse <<
  NCT00354185	Adult Nasal Type Extranodal NK... more >>/T-cell Lymphoma Anaplastic Large Cell Lymphoma Angioimmunoblastic T-cell Lymphoma Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue Intraocular Lymphoma Nodal Marginal Zone B-cell Lymphoma Post-transplant Lymphoproliferative Disorder Recurrent Adult Burkitt Lymphoma Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Adult Diffuse Mixed Cell Lymphoma Recurrent Adult Diffuse Small Cleaved Cell Lymphoma Recurrent Adult Grade III Lymphomatoid Granulomatosis Recurrent Adult Hodgkin Lymphoma Recurrent Adult Immunoblastic Large Cell Lymphoma Recurrent Adult Lymphoblastic Lymphoma Recurrent Adult T-cell Leukemia/Lymphoma Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Mycosis Fungoides/Sezary Syndrome Recurrent Small Lymphocytic Lymphoma Small Intestine Lymphoma Splenic Marginal Zone Lymphoma Stage III Adult Burkitt Lymphoma Stage III Adult Diffuse Large Cell Lymphoma Stage III Adult Diffuse Mixed Cell Lymphoma Stage III Adult Diffuse Small Cleaved Cell Lymphoma Stage III Adult Hodgkin Lymphoma Stage III Adult Immunoblastic Large Cell Lymphoma Stage III Adult Lymphoblastic Lymphoma Stage III Adult T-cell Leukemia/Lymphoma Stage III Cutaneous T-cell Non-Hodgkin Lymphoma Stage III Grade 1 Follicular Lymphoma Stage III Grade 2 Follicular Lymphoma Stage III Grade 3 Follicular Lymphoma Stage III Mantle Cell Lymphoma Stage III Marginal Zone Lymphoma Stage III Mycosis Fungoides/Sezary Syndrome Stage III Small Lymphocytic Lymphoma Stage IV Adult Burkitt Lymphoma Stage IV Adult Diffuse Large Cell Lymphoma Stage IV Adult Diffuse Mixed Cell Lymphoma Stage IV Adult Diffuse Small Cleaved Cell Lymphoma Stage IV Adult Hodgkin Lymphoma Stage IV Adult Immunoblastic Large Cell Lymphoma Stage IV Adult Lymphoblastic Lymphoma Stage IV Adult T-cell Leukemia/Lymphoma Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma Stage IV Grade 1 Follicular Lymphoma Stage IV Grade 2 Follicular Lymphoma Stage IV Grade 3 Follicular Lymphoma Stage IV Mantle Cell Lymphoma Stage IV Marginal Zone Lymphoma Stage IV Mycosis Fungoides/Sezary Syndrome Stage IV Small Lymphocytic Lymphoma Unspecified Adult Solid Tumor, Protocol Specific Waldenström Macroglobulinemia Collapse <<	Phase 1	Terminated	-	United States, Wisconsin ... more >> University of Wisconsin Hospital and Clinics Madison, Wisconsin, United States, 53792 Collapse <<

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• 参考文献

• [1] Yoon S, Eom GH, et al. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med J. 2016 Jan;52(1):1-11.

  [2] Plumb JA, Finn PW, et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2003 Aug;2(8):721-8.

  [3] Sawas A, Radeski D, et al. Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review. Ther Adv Hematol. 2015 Aug;6(4):202-8.

  [4] Dai Y, Chen S, et al. Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res. 2008 Jan 15;14(2):549-58.

  [5] Mottamal M, Zheng S, et al. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules. 2015 Mar 2;20(3):3898-941.

  [6] New M, Olzscha H, et al. HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol. 2012 Dec;6(6):637-56.

  [7] Qian X, Ara G, et al. Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer. 2008 Mar 15;122(6):1400-10.

  [8] Buckley MT, Yoon J, et al. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med. 2007 Oct 12;5:49.

  [9] Warren KE, McCully C, et al. Plasma and cerebrospinal fluid pharmacokinetics of the histone deacetylase inhibitor, belinostat (PXD101), in non-human primates. Cancer Chemother Pharmacol. 2008 Aug;62(3):433-7. Epub 2007 Oct 25.

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