2. Academic Validation
  3. Comparative analysis of the dual EGFR-DNA targeting and growth inhibitory properties of 6-mono-alkylamino- and 6,6-dialkylaminoquinazoline-based type II combi-molecules

Comparative analysis of the dual EGFR-DNA targeting and growth inhibitory properties of 6-mono-alkylamino- and 6,6-dialkylaminoquinazoline-based type II combi-molecules

  • Eur J Med Chem. 2020 Apr 15:192:112185. doi: 10.1016/j.ejmech.2020.112185.
Julie Schmitt 1,  Elliot Goodfellow 1,  Shanlong Huang 1,  Christopher Williams 2,  Izabela N F Gomes 3,  Marcela N Rosa 3,  Rui M Reis 4,  Richard Yang 1,  Hatem M Titi 5,  Bertrand J Jean-Claude 6
Affiliations

Affiliations

  • 1 Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, The Research Institute of the McGill University Health Center/Glen Hospital, Montreal, QC, H4A 3J1, Canada.
  • 2 Scientific Support, Chemical Computing Group Inc., Montreal, QC, H3A 2R7, Canada.
  • 3 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
  • 4 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • 5 Department of Chemistry, McGill University, Montreal, QC, H3A 2K6, Canada.
  • 6 Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, The Research Institute of the McGill University Health Center/Glen Hospital, Montreal, QC, H4A 3J1, Canada. Electronic address: bertrandj.jean-claude@mcgill.ca.
PMID: 32145644 DOI: 10.1016/j.ejmech.2020.112185
Abstract

Over the past decade, we described a novel tumour targeted approach that sought to design "combi-molecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent. Surprisingly, the results showed that JS61, while capable of inducing strong DNA damage, exhibited moderate EGFR inhibitory potency. In contrast, "combi-molecules" with no bulky substituent at the N-6 position (e.g. ZR2002 and JS84) showed stronger EGFR and growth inhibitory potency than JS61 in a panel of lung Cancer cells. To rationalize these results, X-ray crystallography and molecular modeling studies were undertaken, and the data obtained indicated that bulkiness of the 6-N,N-disubstituted moieties hinder its binding to the ATP site and affects binding reversibility.

Keywords

Combi-molecule; DNA damaging agent; Epidermal growth factor receptor (EGFR); Non-small cell lung cancer (NSCLC).

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