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PDBsum entry 6h39
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Contents |
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250 a.a.
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244 a.a.
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240 a.a.
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235 a.a.
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231 a.a.
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243 a.a.
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241 a.a.
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222 a.a.
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204 a.a.
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195 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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Discovery of the first-In-Class dual histone deacetylase-Proteasome inhibitor.
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Authors
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S.Bhatia,
V.Krieger,
M.Groll,
J.D.Osko,
N.Reßing,
H.Ahlert,
A.Borkhardt,
T.Kurz,
D.W.Christianson,
J.Hauer,
F.K.Hansen.
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Ref.
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J Med Chem, 2018,
61,
10299-10309.
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PubMed id
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Abstract
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Dual- or multitarget drugs have emerged as a promising alternative to
combination therapies. Proteasome inhibitors (PIs) possess synergistic activity
with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of
the ubiquitin degradation and aggresome pathways. Here, we present the design,
synthesis, binding modes, and anticancer properties of RTS-V5 as the
first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was
confirmed by biochemical and cellular assays as well as X-ray crystal structures
of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with
leukemia and multiple myeloma cell lines as well as therapy refractory primary
patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and
selective anticancer activity. Our results will thus guide the structure-based
optimization of dual HDAC-proteasome inhibitors for the treatment of
hematological malignancies.
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