Novel Imidazotetrazine Evades Known Resistance Mechanisms and Is Effective against Temozolomide-Resistant Brain Cancer in Cell Culture

Riley L. Svec, Sydney A. Mckee, Matthew R. Berry, Aya M. Kelly, Timothy M. Fan, Paul J. Hergenrother

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor. Currently, frontline treatment for primary GBM includes the DNA-methylating drug temozolomide (TMZ, of the imidazotetrazine class), while the optimal treatment for recurrent GBM remains under investigation. Despite its widespread use, a majority of GBM patients do not respond to TMZ therapy; expression of the O6-methylguanine DNA methyltransferase (MGMT) enzyme and loss of mismatch repair (MMR) function as the principal clinical modes of resistance to TMZ. Here, we describe a novel imidazotetrazine designed to evade resistance by MGMT while retaining suitable hydrolytic stability, allowing for effective prodrug activation and biodistribution. This dual-substituted compound, called CPZ, exhibits activity against cancer cells irrespective of MGMT expression and MMR status. CPZ has greater blood-brain barrier penetrance and comparable hematological toxicity relative to TMZ, while also matching its maximum tolerated dose in mice when dosed once-per-day over five days. The activity of CPZ is independent of the two principal mechanisms suppressing the effectiveness of TMZ, making it a promising new candidate for the treatment of GBM, especially those that are TMZ-resistant.

Original languageEnglish (US)
Pages (from-to)299–313
Number of pages15
JournalACS chemical biology
Volume17
Issue number2
DOIs
StatePublished - Feb 18 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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