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PDBsum entry 6mgo
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Structural protein
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PDB id
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6mgo
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References listed in PDB file
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Key reference
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Title
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Truncated actin-Targeting macrolide derivative blocks cancer cell motility and invasion of extracellular matrix.
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Authors
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B.V.Pipaliya,
D.N.Trofimova,
R.L.Grange,
M.Aeluri,
X.Deng,
K.Shah,
A.W.Craig,
J.S.Allingham,
P.A.Evans.
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Ref.
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J Am Chem Soc, 2021,
143,
6847-6854.
[DOI no: ]
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PubMed id
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Abstract
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Cancer metastasis is a complex process involving highly motile tumor cells that
breach tissue barriers, enter the bloodstream and lymphatic system, and
disseminate throughout the body as circulating tumor cells. The primary cellular
mechanism contributing to these critical events is the reorganization of the
actin cytoskeleton. Mycalolide B (MycB) is an actin-targeting marine macrolide
that can suppress proliferation, migration, and invasion of breast and ovarian
cancer cells at low nanomolar doses. Through structure-activity relationship
studies focused on the actin-binding tail region (C24-C35) of MycB, we
identified a potent truncated derivative that inhibits polymerization of G-actin
and severs F-actin by binding to actin's barbed end cleft. Biological analyses
of this miniature MycB derivative demonstrate that it causes a rapid collapse of
the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility
and invasion of the extracellular matrix (ECM) by inhibiting
invadopodia-mediated ECM degradation. These studies provide essential
proof-of-principle for developing actin-targeting therapeutic agents to block
cancer metastasis and establish a synthetically tractable barbed end-binding
pharmacophore that can be further improved by adding targeting groups for
precision drug design.
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