生物活性

• 描述CC-115 is a dual inhibitor of mammalian target of rapamycin kinase (mTOR) and DNA-dependent protein kinase (DNA-PK), two members in the PI3K family. It inhibits TORK and DNA-PK with IC₅₀ values of 0.021 and 0.013 µM, respectively^[3]. In primary chronic lymphocytic leukemia (CLL) cells, CC-115 at 0.1-0.35 µM dose-dependently suppressed Ser-2056 phosphorylation on DNA-PK and bleomycin-induced Ser-1981 phosphorylation on ATM. CC-115 at 1 µM significantly inhibited irradiation (5 Gy)-induced γH2AX level in ATM/11q mutated CLL cells. Low dose CC-115 (0.35 µM) successfully blocked the constitutive phosphorylation of S6, a marker for mTORC1 activity, in all CLL cells. It also completely inhibited the phosphorylation of the mTORC1 and mTORC1 targets in BCR-stimulated CLL cells at the concentration of 1 µM. CC-115 induced caspase-dependent cell death in resting CLL cells with an IC₅₀ value of 0.51 µM. CC-115 at the dose of 1 µM reverted CD40-mediated resistance to chemotherapy or venetoclax in CLL cells cultured on CD40L-expressing fibroblasts. CC-115 treatment (1 µM) also efficiently inhibited the proliferation of CLL cells^[4]. In PC-3 tumor-bearing mice, administration of CC-115 at 0.25, 0.5 and 1 mg/kg twice daily or 1 mg/kg once daily resulted in the tumor volume reduction of 46%, 57%, 66% and 57%, respectively.
• 作用机制CC-115 inhibits both mTOR and DNA-PK by extending the 7-substituent into the kinase catalytic pocket to inhibit their activities.
• 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
  NCT02833883	Prostate Cancer ... more >> Castration Resistant Prostate Cancer Collapse <<	Phase 1	Recruiting	July 2019	United States, California ... more >> University of California San Francisco Recruiting San Francisco, California, United States, 94143 Contact: Felix Feng, MD    415-502-7222       United States, Maryland John Hopkins Medical Center Recruiting Baltimore, Maryland, United States, 21287 Contact: Emmanuel Antonarakis, MBBCh    410-464-6641       Principal Investigator: Emmanuel Antonarakis, MBBCh          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Dana Rathkopf, MD    646-422-4379       Contact: Wassim Abida, MD, PhD    646-422-4633       Principal Investigator: Dana Rathkopf, MD          United States, Washington University of Washington School of Medicine Recruiting Seattle, Washington, United States, 98109 Contact: Heather Cheng, MD, PhD    206-606-7486       Principal Investigator: Heather Cheng, MD, PhD Collapse <<
  NCT02977780	Glioblastoma	Phase 2	Recruiting	May 2021	United States, Alabama ... more >> University of Alabama at Birmingham Not yet recruiting Birmingham, Alabama, United States, 35294 Contact: L. Burt Nabors, MD    205-934-1432    bnabors@uab.edu    United States, Massachusetts Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, 02114 Contact: Isabel Arrillaga-Romany, MD PhD    617-724-8770    iarrillaga@mgh.harvard.edu    Principal Investigator: Isabel Arrillaga-Romany, MD PhD          Dana Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02115 Contact: Brian Alexander, MD MPH    617-732-7560    Brian_Alexander@dfci.harvard.edu    Contact: Lisa Doherty, NP    617-632-2166    lisa_doherty@dfci.harvard.edu    Principal Investigator: Brian Alexander, MD MPH          United States, Minnesota Mayo Clinic Not yet recruiting Rochester, Minnesota, United States, 55905 Contact: Eva Galanis, MD    507-284-2511    galanis.evanthia@mayo.edu    United States, New York Columbia University Medical Center Recruiting New York, New York, United States, 10032 Contact: Mary Welch, MD    212-342-0571    mw2517@cumc.columbia.edu    United States, Ohio Cleveland Clinic Recruiting Cleveland, Ohio, United States, 44195 Contact: Manmeet Ahluwalia,, MD    216-444-6145    ahluwam@ccf.org    United States, Pennsylvania University of Pittsburgh Medical Center Recruiting Pittsburgh, Pennsylvania, United States, 15232 Contact: Jan Drappatz, MD    412-864-7791    drappatzj@upmc.edu    United States, Texas UT MD Anderson Cancer Center Not yet recruiting Houston, Texas, United States, 77030 Contact: John DeGroot, MD    713-745-3072    jdegroot@mdanderson.org    United States, Utah Huntsman Cancer Institute Recruiting Salt Lake City, Utah, United States, 84112 Contact: Howard Colman, MD    801-587-4042    Howard.colman@hci.utah.edu    United States, Virginia University of Virginia Health System Recruiting Charlottesville, Virginia, United States, 22908 Contact: David Schiff, MD    434-924-5610    Ds4jd@virginia.edu Collapse <<
  NCT01353625	Glioblastoma Multiforme ... more >> Squamous Cell Carcinoma of Head and Neck Prostate Cancer Ewing's Osteosarcoma Chronic Lymphocytic Leukemia Neoplasm Metastasis Collapse <<	Phase 1	Active, not recruiting	November 30, 2019	United States, California ... more >> Cedars-Sinai Medical Center Los Angeles, California, United States, 90048 UCLA Los Angeles, California, United States, 90095 University of California, San Francisco Comprehensive Cancer Center and Cancer Research Institiute San Francisco, California, United States, 94115 United States, Florida Moffitt Cancer Center Tampa, Florida, United States, 33612 United States, Michigan University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109 Henry Ford Health System Detroit, Michigan, United States, 48202 United States, New York Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10021 United States, Tennessee Sarah Cannon Research Institute Drug Development Unit Nashville, Tennessee, United States, 37203 United States, Texas Mary Crowley Medical Research Center Dallas, Texas, United States, 75201 The University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77303 France Institut Gustave Roussy Villejuif Cedex, France, 94805 Germany Uniklinik Koln Koeln, Germany, 50937 Universitatsklinikum Wurzburg Würzburg, Germany, 97070 Spain Hospital Vall d'Hebron Barcelona, Spain, 08035 Hospital Universitario Madrid Sanchinarro Madrid, Spain, 28050 Hospital de Donosti San Sebastián (Guipuzcoa), Spain, 20014 Hospital Virgen del Rocio Sevilla, Spain, 41013 Collapse <<

• 参考文献

• [1] Thijssen R, Ter Burg J, et al. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016 Jul 28;128(4):574-83.

  [2] Mortensen DS, Perrin-Ninkovic SM, et al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-608.

  [3] Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Elsner J, Zhao J, Whitefield B, Tehrani L, Sapienza J, Riggs JR, Parnes JS, Papa P, Packard G, Lee BG, Harris R, Correa M, Bahmanyar S, Richardson SJ, Peng SX, Leisten J, Khambatta G, Hickman M, Gamez JC, Bisonette RR, Apuy J, Cathers BE, Canan SS, Moghaddam MF, Raymon HK, Worland P, Narla RK, Fultz KE, Sankar S. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-608. doi: 10.1021/acs.jmedchem.5b00627. Epub 2015 Jul 8. PMID: 26102506.

  [4] Thijssen R, Ter Burg J, Garrick B, van Bochove GG, Brown JR, Fernandes SM, Rodríguez MS, Michot JM, Hallek M, Eichhorst B, Reinhardt HC, Bendell J, Derks IA, van Kampen RJ, Hege K, Kersten MJ, Trowe T, Filvaroff EH, Eldering E, Kater AP. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016 Jul 28;128(4):574-83. doi: 10.1182/blood-2016-02-700328. Epub 2016 May 27. PMID: 27235137.