title: Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Senese
authors.affiliation: 1] Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA [2] Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Lo
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Zangle
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Gholkar
authors.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Robert
authors.affiliation: Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Homet
authors.affiliation: 1] Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA [2] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA [3] Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA [4] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ribas
authors.affiliation: The Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Summers
authors.affiliation: 1] Department of Bioengineering, University of California, Los Angeles, CA, USA [2] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA [3] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA [4] Broad Stem Cell Research Center, University of California, Los Angeles, CA, USA [5] California NanoSystems Institute, University of California, Los Angeles, CA, USA [6] Molecular Biology Institute, University of California, Los Angeles, CA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Teitell
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Damoiseaux
authors.affiliation: 1] Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA [2] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA [3] Molecular Biology Institute, University of California, Los Angeles, CA, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Torres
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D055808:Drug Discovery; D006367:HeLa Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D015335:Molecular Probes / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D058105:Polymerization / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015335:Molecular Probes; D054852:Small Molecule Libraries; D014404:Tubulin