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PDBsum entry 6g7f
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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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226 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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229 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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Design, Synthesis, And evaluation of cystargolide-Based β-Lactones as potent proteasome inhibitors.
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Authors
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D.Niroula,
L.P.Hallada,
C.Le chapelain,
S.K.Ganegamage,
D.Dotson,
S.Rogelj,
M.Groll,
R.Tello-Aburto.
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Ref.
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Eur J Med Chem, 2018,
157,
962-977.
[DOI no: ]
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PubMed id
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Abstract
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The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were
used to conduct structure-activity relationship (SAR) studies in order to assess
their anticancer potential. A total of 24 different analogs were designed,
synthesized and evaluated for proteasome inhibition, for cytotoxicity towards
several cancer cell lines, and for their ability to enter intact cells. X-ray
crystallographic analysis and subunit selectivity was used to determine the
specific subunit binding associated with the structural modification of the
β-lactone (P1), peptidic core, (Px and Py),
and end-cap (Pz) of our scaffold. The cystargolide derivative 5k,
structurally unique at both Py and P1, exhibited the most
promising inhibitory activity for the β5 subunit of human proteasomes
(IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7
(IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and
RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular
infiltration assays revealed that minor structural modifications have
significant effects on the ability of our PIs to inhibit intracellular
proteasomes, and we identified 5k as a promising candidate for continued
therapeutic studies. Our novel drug lead 5k is a more potent proteasome
inhibitor than carfilzomib with mid-to-low nanomolar IC50
measurements and it is cytotoxic against multiple cancer cell lines at levels
approaching those of carfilzomib.
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