Abstract 1878: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib

Abstract

Abstract Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Bortezomib, carfilzomib, and ixazomib, which are approved for clinical use, have shown some cardiotoxicity. Carfilzomib and oprozomib are epoxyketones that form an irreversible bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. A primary neonatal rat myocyte model was used to study these cardiotoxic mechanisms. Using LDH release as a measure of damage in the myocyte model, after drug treatments of either 1, 4 and 72 hr all these drugs induced myocyte damage at low- to sub-micromolar concentrations. Oprozomib induced significantly less myocyte damage than any of the other drugs. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome were also determined in order to see if differences in the binding kinetics could explain the degree of myocyte damage. Oprozomib inhibited the 20S proteasome with a second-order binding “on” rate constant that was 60-fold slower than for ixazomib, the fastest binding drug. The first-order dissociation “off” rate constants for the three boronic acids were also determined. Delanzomib dissociated from its complex with the 20S proteasome with a half-time that was more than 20-fold slower than for ixazomib, the fastest dissociating drug. In conclusion, while all these drugs were potently toxic to myocytes at submicromolar concentrations, oprozomib was considerably less toxic than any of the other drugs. As a group the boronic acid drugs were not significantly more toxic than the epoxyketone drugs. The dissociation half-times of the boronic acid complexes were also not correlated with myocyte damage. The fact that oprozomib bound to the 20S proteasome more slowly than any of the other drugs may be the reason, in part, that it is less toxic. Support: CIHR; a Canada Research Chair in Drug Development. Citation Format: Brian B. Hasinoff. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1878.