Revamping a brain cancer drug

Abstract

Glioblastoma—a type of aggressive, invasive brain tumor—is almost always fatal. Although treatments exist, there is no cure. Now, researchers have taken a fresh look at a drug used to treat glioblastoma, temozolomide (TMZ), and made it a better cancer killer with potential for fewer side effects (ACS Chem. Biol. 2018, DOI:10.1021/acschembio.8b00864). Because only 17% of TMZ gets through the blood-brain barrier, Paul J. Hergenrother of the University of Illinois, Urbana-Champaign, and colleagues wanted to see if they could tweak the molecule’s structure to help it pass into the brain without compromising its anticancer properties. The team swapped out TMZ’s amide group for a series of chemical groups hypothesized to improve brain penetration and then tested the compounds, first in cancer cells and then in mice. The best-performing compound, K-TMZ, contains a methyl ketone group instead of the amide and showed greatly increased brain permeability, with 69% entering the brain compared