生物活性

• 描述KW-2478 is a nonansamycin Hsp90 inhibitor with IC50 value of 3.8nM. Compared with the previous Hsp90 inhibitor like 17-AAG, it overcomes limitations such as low water solubility and hepatotoxicity. Treatment with KW-2478 at concentration ranging in 0.1-10μM and time course in 12-72h led inhibition of OPM-2/GFP and NCI-H929 cell viability in a time- and dose-dependent manner. This may be associated with degradation of well-known Hsp90 client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1). KW-2478 at 3μM depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor in OPM-2/GFP, RPMI 8226, and U266 cells at 6h, 12h and 24h in a time-dependent manner. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. Administration of KW-2478 at 25mg/kg or 100mg/kg, i.v., twice daily for 5 days, suppressed tumor growth in NCI-H929 s.c. inoculated model, accompanied with the degradation of client proteins in tumors. Administration of KW-2478 at 100mg/kg, i.v., twice daily for 5 days showed a significant reduction of both serum M protein (measured on day 31, 38 and 45) and MM tumor burden in the bone marrow of a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein.
• 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
  NCT01063907	Multiple Myeloma	Phase 1 Phase 2	Completed	-	United States, Arizona ... more >> Arizona Clinical Research Center, Inc. / Arizona Oncology Associates, 1825 N Kolb, Tucson, Arizona, United States, 85715 United States, California Pacific Shores Medical Group 1043 Elm Ave, Suite 104 Long Beach, California, United States, 90813 UCLA Medical Center Hematology / Oncology Division, 10945 Le Conte Ave #2333, Los Angeles, California, United States, 90095-7059 United States, Florida Collaborative Research Group 2320 S Seacrest Blvd, Suite 202 Boynton Beach, Florida, United States, 33435 United States, Illinois Rush University Medical Center / Division of Hematology/Oncology Research 1725 W Harrison Street, Suite 834 Chicago, Illinois, United States, 60612 United States, New Jersey Cancer Institute of New Jersey 195 Little Albany Street New Brunswick, New Jersey, United States, 08903-2681 United States, Tennessee The Jones Clinic 7710 Wolf River Circle Germantown, Tennessee, United States, 38138 United States, Texas UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, United States, 77030 United States, Wisconsin Gundersen Clinic Center for Cancer and Blood Disorders, 1900 South Ave, EB2-001, La Crosse, Wisconsin, United States, 54601 Philippines National Kidney and Transplant Institute, Rm 3215 Doctors Clinic, East Avenue Diliman, Quezon City, Philippines Makati Medical Center, New Wing Hall C372, #2 Amorsolo Street, Legaspi Village, Makati City, Philippines The Medical City, 1609 MATI Building, The Medical City, Ortigas Avenue, Pasig City, Metro Manila, Philippines Saint Lukes Medical Center, Rm 222 MAB Saint Lukes Medical Center, E. Rodriguez Quezon City, Philippines United Kingdom Darent Valley Hospital Dept of Haematology, Acorn House, Darenth Wood Road Dartford, Kent, United Kingdom, DA2 8DA St Bartholomew's Hospital Haematology Department, 1st Floor, Pathology Dominion House, 59 Bartholomew Close, London, United Kingdom, EC1 7ED Christie Hospital - Department Haematology, 550 Wilmslow Road Withington, Manchester, Greater Manchester, United Kingdom, M20 4BX Hillingdon Hospital Dept of Haematology, Pield Health Road Uxbridge, Middlesex, United Kingdom, UB8 3NN Nottingham University Hospitals NHS Trust, Centre for Clinical Haemotology Hucknall Road, Nottingham, United Kingdom, NG5 1PB Royal Marsden Hospital, Orchard House Downs Road, Sutton, Surrey, United Kingdom, SM2 5PT Royal Bournemouth Hospital, Dept. of Haematolgy, Castle Lane East, Bournemouth, United Kingdom, BH7 7DW Royal Devon & Exeter Hospital Haematology Centre, Barrack Road Exeter, United Kingdom, EX2 5DW Northwick Park Hospital Dept of Haematology, Watford Road Harrow, United Kingdom, HA1 3UJ St James Hospital, St James' Institute of Oncology, Department of Haematology, Level 03, Bexley Wing, Leeds, United Kingdom, LS9 7TF UCL Cancer Institute, Paul O'Gorman Building, University College London,72 Huntley Street London, United Kingdom, WC1E 6DD Manchester Royal Infirmary Dept of Haematology, Oxford Road Manchester, United Kingdom, M13 9WL Royal Cornwall Hospital Haematology Clinic Truro, United Kingdom, TR1 3LS Collapse <<
  NCT00457782	Multiple Myeloma ... more >> Chronic Lymphocytic Leukaemia B-cell Non-Hodgkin's Lymphoma Collapse <<	Phase 1	Completed	-	United Kingdom ... more >> St Bartholomew's Hospital London, United Kingdom UCLH London, United Kingdom Christie Hospital Manchester, United Kingdom Nottingham University NHS Trust Nottingham, United Kingdom Cancer Research UK Clinical Centre Southampton, United Kingdom Royal Marsden Hospital Sutton, United Kingdom Collapse <<
  NCT01063907	-	-	Completed	-	-

• 参考文献

• [1] Nakashima T, Ishii T, et al. New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin Cancer Res. 2010 May 15;16(10):2792-802.

  [2] Yong K, Cavet J, et al. Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies. Br J Cancer. 2016 Jan 12;114(1):7-13.