生物活性

• 描述PCI-24781 is a novel hydroxamic acid–based pan-HDAC inhibitor with Ki values of 7nM, 19nM, 8.2nM, 17nM, 280nM and 24nM for HDAC1 HDAC2, HDAC3/SMRT, HDAC6, HDAC8 and HDAC10. Treatment with PCI-24781 at concentration ranging in 0.5-10μM resulted in the accumulation of acetylated histone and acetylated tubulin in a dose-dependent manner, accompanied with increase of p21, and resulted in an inhibition of tumor cell growth and the induction of apoptosis shown by increased γH2AX and cleaved PARP in HCT116, DLD-1 and HUVEC cells. Administration of PCI-24781 (i.v., formulated in 30% HP-cyclodextrin) to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth. Inhibition of HDAC enzymes by PCI-24781 led to a significant reduction in the transcription of genes specifically associated with HR, including RAD51. RAD51 protein levels were significantly decreased after 24 h of drug exposure both in vitro and in vivo.
• 作用机制PCI-24781 is a hydroxamic acid–based inhibitor which can chelate the Zn²⁺ of HDAC.^[1]

• 动物研究
  剂量	Mice: 12.5 mg/kg[3] (i.p.), 50 mg/kg[4] (i.p.) Nude Mice: 10 mg/kg - 200 mg/kg[1] (i.v.)
  给药途径	i.p., i.v.
  动物药代数据	Animal Nude mice[1] Dose 10 mg/kg Administration i.v. T1/2 6.7 min CL 297 ml/min/kg

• 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
  NCT00473577	Hematologic Neoplasms ... more >> Neoplasms Collapse <<	Phase 1	Completed	-	United States, Illinois ... more >> University of Chicago Chicago, Illinois, United States, 60643 Collapse <<
  NCT03590054	Stage III Cutaneous Melanoma ... more >> Stage IV Cutaneous Melanoma Locally Advanced Melanoma Locally Advanced Solid Neoplasm Metastatic Head and Neck Squamous Cell Carcinoma Metastatic Malignant Solid Neoplasm Metastatic Melanoma Metastatic Urothelial Carcinoma Non-Small Cell Lung Carcinoma Stage IB Lung Cancer AJCC v7 Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8 Stage III Lung Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8 Stage IV Lung Cancer AJCC v8 Stage IV Ureter Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Collapse <<	Phase 1	Recruiting	April 15, 2020	United States, California ... more >> University of California, San Francisco Recruiting San Francisco, California, United States, 94143 Contact: Rahul Aggarwal, MD    877-827-3222    clinicaltrials@ucsf.edu Collapse <<
  NCT03592472	Renal Cell Carcinoma	Phase 3	Recruiting	January 17, 2022	United States, California ... more >> University of California Davis Comprehensive Cancer Center Recruiting Sacramento, California, United States, 95817 Contact: Parikh Mamta          United States, Kentucky Norton Cancer Institute, Norton Healthcare Pavilion Not yet recruiting Louisville, Kentucky, United States, 40202 Contact: Kalebasty Arash          United States, Louisiana Ochsner Clinic Foundation Recruiting New Orleans, Louisiana, United States, 70121 Contact: Matrana Marc          United States, Nebraska GU Research Network/Urology Cancer Center Recruiting Omaha, Nebraska, United States, 68130 Contact: Nordquist Luke          Nebraska Cancer Specialists Recruiting Omaha, Nebraska, United States, 68130 Contact: Hauke Ralph          United States, New York Northwell Health/Monter Cancer Center Recruiting Lake Success, New York, United States, 11042 Contact: Bradley Thomas          United States, Ohio Precision Cancer Research/Dayton Physicians Network - Treatment Recruiting Kettering, Ohio, United States, 45409 Contact: Bane Charles          United States, Pennsylvania St. Luke's Hospital Recruiting Easton, Pennsylvania, United States, 18045 Contact: Faroun Yacoub          United States, Texas HOPE Cancer Center of East Texas Recruiting Tyler, Texas, United States, 75701 Contact: Lee Arielle          United States, Washington Medical Oncology Associates, PS (dba Summit Cancer Centers) Recruiting Spokane, Washington, United States, 99208 Contact: Arvind Chaudhry          Korea, Republic of National Cancer Center - Center For Prostate Cancer Not yet recruiting Goyang-si, Korea, Republic of, 10408 Contact: Jinsoo Chung          CHA Bundang Medical Center, CHA University Not yet recruiting Seongnam-si, Korea, Republic of, 13496 Contact: Chan Kim          Severance Hospital, Yonsei University Health System - Medical Oncology Not yet recruiting Seoul, Korea, Republic of, 03722 Contact: Sun Young Rha          Asan Medical Center - University of Ulsan College of Medicin Not yet recruiting Seoul, Korea, Republic of, 05505 Contact: Jae Lyun Lee          Samsung Medical Center - Hematology-Oncology Not yet recruiting Seoul, Korea, Republic of, 06351 Contact: Se Hoon Park Collapse <<

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• 参考文献

• [1] Buggy JJ, Cao ZA, et al. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther. 2006 May;5(5):1309-17.

  [2] Adimoolam S, Sirisawad M, et al. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19482-7. Epub 2007 Nov 27.

  [3] Sholler GS, Currier EA, et al. PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. J Cancer Ther Res. 2013 Dec 28;2:21.

  [4] Lopez G, Liu J, et al. Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res. 2009 May 15;15(10):3472-83.