Interaction of bovine brain tubulin with the 4(1H)-pyrizinone derivative IKP104, an antimitotic drug with a complex set of effects on the conformational stability of the tubulin molecule

Citations Over TimeTop 13% of 1995 papers

Abstract

The ligands of tubulin have proved to be excellent probes for the conformation of the tubulin molecule. The most varied in their effects on tubulin are those ligands which are competitive or noncompetitive inhibitors of vinblastine binding. The 4(H)-pyrizinone derivative 2-(4-fluorophenyl)-1-(2-chloro- 3,5-dimethoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone [sequence: see text] (IKP104) is a novel antimitotic drug which inhibits microtubule assembly in vitro and in vivo and polymerizes tubulin into spiral filaments. Using a fluorescence assay, we found that IKP104 appears to bind to tubulin at two classes of site, differing in affinity. IKP104 also blocks formation of an intrachain cross-link in beta-tubulin, induced by N,N"-ethylenebis(iodoacetamide), linking Cys12 to either Cys201 or Cys211. IKP104 appears to belong to that group of tubulin ligands which includes vinblastine, maytansine, rhizoxin, phomopsin A, dolastatin 10, and halichondrin B. An unusual effect of IKP104 is that it greatly enhances the decay or apparent unfolding or opening of the tubulin molecule. The sulfhydryl titer of tubulin is doubled and the exposure of hydrophobic areas on the tubulin molecule is tripled by IKP104. These effects of IKP104 are counteracted by vinblastine, maytansine, and phomopsin A, suggesting that IKP104 may be competing with these other drugs for binding to tubulin. However, the effects are also counteracted by colchicine and podophyllotoxin, implying a more complex effect, namely, that IKP104 and colchicine, even when both are bound to tubulin, are competing for their effects on the same domain of tubulin. Surprisingly, when IKP104 is used in conjunction with colchicine, binding of colchicine to tubulin is strongly stabilized.(ABSTRACT TRUNCATED AT 250 WORDS)

Related Papers

• → Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle(1998)641 cited
• → Ustiloxins, new antimitotic cyclic peptides: Interaction with porcine brain tubulin(1995)98 cited
• → Interactions of the Sponge-Derived Antimitotic Tripeptide Hemiasterlin with Tubulin: Comparison with Dolastatin 10 and Cryptophycin 1(1999)89 cited
• → Interaction of Arenastatin A with Porcine Brain Tubulin.(1997)28 cited
• → Ring Polymers of Tubulin Induced by Binding of Natural Antimitotic Peptides(2005)1 cited