TY - JOUR
T1 - Novel Imidazotetrazine Evades Known Resistance Mechanisms and Is Effective against Temozolomide-Resistant Brain Cancer in Cell Culture
AU - Svec, Riley L.
AU - Mckee, Sydney A.
AU - Berry, Matthew R.
AU - Kelly, Aya M.
AU - Fan, Timothy M.
AU - Hergenrother, Paul J.
N1 - Funding Information:
We thank L. Li (Metabolomics Center, Roy J. Carver Biotechnology Center, UIUC) for LC–MS/MS analysis and L. Dirikolu (School of Veterinary Medicine, LSU) for PK analysis. This work was supported by the University of Illinois and the NCI (R01-CA256481). R.L.S. and S.A.M. are members of the NIH Chemistry–Biology Interface Training Grant (T32-GM136629). Thermal stability analysis of compounds was carried out in part in the Materials Research Laboratory Central Research Facilities, University of Illinois.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/2/18
Y1 - 2022/2/18
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.2c00022
DO - 10.1021/acschembio.2c00022
M3 - Article
C2 - 35119837
AN - SCOPUS:85124289020
SN - 1554-8929
VL - 17
SP - 299
EP - 313
JO - ACS chemical biology
JF - ACS chemical biology
IS - 2
ER -