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

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

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.

Affiliation

Senese S; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Lo YC; 1] Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA [2] Department of Bioengineering, University of California, Los Angeles, CA, USA.
Huang D; Department of Bioengineering, University of California, Los Angeles, CA, USA.
Zangle TA; Department of Bioengineering, University of California, Los Angeles, CA, USA.
Gholkar AA; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Robert L; Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Homet B; Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Ribas A; 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
Summers MK; The Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
Teitell MA; 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, C
Damoiseaux R; California NanoSystems Institute, University of California, Los Angeles, CA, USA.
Torres JZ; 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.

Cell Death Dis ; 5: e1462, 2014 Oct 16.

Article in En | MEDLINE | ID: mdl-25321469

ABSTRACT

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.

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Molecular Probes / Cell Cycle / Drug Discovery / High-Throughput Screening Assays / Antineoplastic Agents Limits: Humans Language: En Journal: Cell Death Dis Year: 2014 Document type: Article Affiliation country: Estados Unidos

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