Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development

Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed an...

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Bibliographic Details
Published in:Cell death & disease 2014-10, Vol.5 (10), p.e1462-e1462
Main Authors: Senese, S, Lo, Y C, Huang, D, Zangle, T A, Gholkar, A A, Robert, L, Homet, B, Ribas, A, Summers, M K, Teitell, M A, Damoiseaux, R, Torres, J Z
Format: Article
Language:English
Subjects:
631/67/1059/153
631/67/1813/1634
631/80/641
631/80/82/23
Antibodies
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Cycle - drug effects
Cell Death - drug effects
Drug Discovery
HeLa Cells
High-Throughput Screening Assays - methods
Humans
Immunology
Life Sciences
M Phase Cell Cycle Checkpoints - drug effects
Mitosis - drug effects
Molecular Probes - pharmacology
Neoplasms - drug therapy
Original
original-article
Phenotype
Polymerization - drug effects
Small Molecule Libraries - analysis
Small Molecule Libraries - pharmacology
Tubulin - metabolism
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Summary:Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAF V600E melanomas.
ISSN:2041-4889
2041-4889
DOI:10.1038/cddis.2014.420