2. Academic Validation
  3. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C

Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C

  • Nature. 2014 Oct 30;514(7524):646-9. doi: 10.1038/nature13660.
Katharine L Sackton 1,  Nevena Dimova 1,  Xing Zeng 1,  Wei Tian 2,  Mengmeng Zhang 3,  Timothy B Sackton 4,  Johnathan Meaders 3,  Kathleen L Pfaff 5,  Frederic Sigoillot 5,  Hongtao Yu 6,  Xuelian Luo 7,  Randall W King 3
Affiliations

Affiliations

  • 1 1] Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA [2].
  • 2 1] Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA [2] Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China (W.T.); Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA (K.L.P.); Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (F.S.). [3].
  • 3 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
  • 4 Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, Massachusetts 02138, USA.
  • 5 1] Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA [2] Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China (W.T.); Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA (K.L.P.); Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (F.S.).
  • 6 1] Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA [2] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA.
  • 7 Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA.
PMID: 25156254 DOI: 10.1038/nature13660
Abstract

Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin Ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the Proteasome. Because blocking mitotic exit is an effective approach for inducing tumour cell death, the APC/C represents a potential novel target for Cancer therapy. APC/C activation in mitosis requires binding of Cdc20 (ref. 5), which forms a co-receptor with the APC/C to recognize substrates containing a destruction box (D-box). Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identify a small molecule, called apcin (APC Inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-l-arginine methyl ester, a small molecule that blocks the APC/C-Cdc20 interaction. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110287
    99.71%, APC/C Inhibitor
    APC