Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

Nat Chem Biol. 2020 May;16(5):546-555. doi: 10.1038/s41589-020-0495-z. Epub 2020 Mar 9.


The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that initiates anaphase and mitotic exit. APC/C is activated by Cdc20 and inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin as a small molecule ligand of Cdc20 that inhibits APC/CCdc20 and prolongs mitosis. Here we find that apcin paradoxically shortens mitosis when SAC activity is high. These opposing effects of apcin arise from targeting of a common binding site in Cdc20 required for both substrate ubiquitination and MCC-dependent APC/C inhibition. Furthermore, we found that apcin cooperates with p31comet to relieve MCC-dependent inhibition of APC/C. Apcin therefore causes either net APC/C inhibition, prolonging mitosis when SAC activity is low, or net APC/C activation, shortening mitosis when SAC activity is high, demonstrating that a small molecule can produce opposing biological effects depending on regulatory context.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Anaphase-Promoting Complex-Cyclosome / antagonists & inhibitors*
  • Anaphase-Promoting Complex-Cyclosome / metabolism
  • Binding Sites
  • Carbamates / pharmacology*
  • Cdc20 Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cyclin B1 / metabolism
  • Diamines / pharmacology*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Mitosis / drug effects*
  • Nocodazole / pharmacology
  • Nuclear Proteins / metabolism
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism
  • Telomerase / genetics
  • Telomerase / metabolism
  • Time-Lapse Imaging
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • CCNB1 protein, human
  • Carbamates
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Cyclin B1
  • Diamines
  • MAD2L1BP protein, human
  • Nuclear Proteins
  • apcin
  • CDC20 protein, human
  • Anaphase-Promoting Complex-Cyclosome
  • TERT protein, human
  • Telomerase
  • Nocodazole