期刊
ACS CHEMICAL BIOLOGY
卷 17, 期 2, 页码 299-313出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.2c00022
关键词
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资金
- University of Illinois
- NCI [R01-CA256481]
- NIH Chemistry-Biology Interface Training Grant [T32-GM136629]
This article describes a novel compound, CPZ, which shows promising activity against GBM by overcoming MGMT resistance and being effective regardless of MMR status. CPZ has better blood-brain barrier penetration and comparable tolerability to TMZ, making it a potential candidate for GBM treatment, especially in TMZ-resistant cases.
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 O-6-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.
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