The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation.
HMN-176 is a potential new cancer therapeutic known to retard the proliferation of tumor cell lines. Here, we show that this compound inhibits meiotic spindle assembly in surf clam oocytes and delays satisfaction of the spindle assembly checkpoint in human somatic cells by inducing the formation of short and/or multipolar spindles. HMN-176 does not affect centrosome assembly, nuclear envelope breakdown, or other aspects of meiotic or mitotic progression, nor does it affect the kinetics of Spisula or mammalian microtubule (MT) assembly in vitro. Notably, HMN-176 inhibits the formation of centrosome-nucleated MTs (i.e., asters) in Spisula oocytes and oocyte extracts, as well as from isolated Spisula or mammalian centrosomes in vitro. Together, these results reveal that HMN-176 is a first-in-class anticentrosome drug that inhibits proliferation, at least in part, by disrupting centrosome-mediated MT assembly during mitosis.
DiMaio
Michael A
MA
Department of Biology and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
Mikhailov
Alexei
A
Rieder
Conly L
CL
Von Hoff
Daniel D
DD
Palazzo
Robert E
RE
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002417:Cattle; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D049890:Spisula; D014407:Tumor Cells, Cultured
C479799:(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide; D001597:Benzylidene Compounds; D011725:Pyridines