In:
Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3477-3477
Kurzfassung:
Multiple Myeloma (MM) is characterized by the malignant proliferation of plasma cells and high osteoclast (OCL) activity resulting in increased bone destruction and the development of lytic lesions. Ideally, novel therapeutic agents directed at MM should not only target the myeloma cell, but also OCL activity. Multiple, chemically distinct, Histone Deacetylase (HDAC) inhibitors have shown promising anti-myeloma activity in pre-clinical studies. The majority of the HDAC inhibitors in clinical development employ either benzamide or hydroxamate chemistry. Through an uHTS biochemical screen of 600,000 compounds and subsequent medicinal chemistry efforts, a novel mercaptoketone series of HDAC inhibitors has been developed. The most potent compounds in this series exhibit nanomolar activity in both biochemical and cell-based assays. To determine the clinical potential of this series in treating MM we have profiled the lead compound, KD5170 in assays that monitor osteoclastogenesis and proliferation and apoptosis of MM cells. To evaluate the effects of KD5170 on the formation of OCL from mononuclear hematopoietic precursors, we utilized a human bone marrow culture system from MM patients to generate OCLs by in vitro RANKL/M-CSF stimulation. KD5170 treatment resulted in a significant dose dependent (0.5–8 10−6M) inhibition of osteoclast formation. In addition, RPMI-8226 cell proliferation was significantly suppressed by KD5170 at 3 10−6M as measured by [3H]-Thymidine-incorporation. Furthermore, we observed that KD5170 induced dose- (0.05–1 10−6M) and time-dependent (2–24h) apoptosis of U266 MM cells, as measured by Hoechst/PI double staining to identify distinct stages of apoptosis and to differentiate between apoptotic and necrotic cell death. Significantly, less than 5% of the cells were necrotic (PI-positive) indicating active engagement of the apoptotic pathway. KD5170 treatment (1 10−6M, 72 h) also markedly decreased the viability of primary CD138+ bone marrow cells from MM patients, as determined by trypan blue exclusion. In contrast, the viability of CD138− and mononuclear bone marrow cells from MM patients and normal healthy donors were unaffected, sug gesting targeted selectivity. Our studies identify KD5170 as a promising new HDAC inhibitor that inhibits both osteoclast formation as well as the proliferation of MM cells. Furthermore, pronounced anti-proliferative activity of KD5170 on the MM cell line U266, suggests that a subset of MM may be the ideal target of this agent. U266 harbors a translocation involving 11q13 raising the possibility that this chromosomal alteration and Cyclin D1 dysregulation may have a role in mediating KD5170 sensitivity and as such will be a focus of future studies.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V108.11.3477.3477
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2006
ZDB Id:
1468538-3
ZDB Id:
80069-7
