Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

British Journal of Cancer
Ranjita BanerjeeBertrand J Jean-Claude

Abstract

Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed 'Cascade-release targeting' that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene express...Continue Reading

References

Oct 1, 1985·Environmental Health Perspectives·W J BodellM L Rosenblum
Jan 1, 1995·Progress in Nucleic Acid Research and Molecular Biology·A E PeggR C Moschel
Sep 1, 1996·Clinical & Experimental Metastasis·T TurnerA Wells
Feb 1, 1997·European Journal of Obstetrics, Gynecology, and Reproductive Biology·H Meden, W Kuhn
Sep 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·D W FryE M Dobrusin
Mar 30, 2000·International Journal of Cancer. Journal International Du Cancer·A M Tari, G Lopez-Berestein
Feb 7, 2001·Mutation Research·J P McNameeP V Bellier
Nov 4, 2000·Biochemical and Biophysical Research Communications·X ChenZ Wang
May 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Malcolm RansonEric K Rowinsky
Sep 18, 2002·The Journal of Pharmacology and Experimental Therapeutics·Fouad BrahimiBertrand J Jean-Claude
Dec 24, 2002·Cancer Chemotherapy and Pharmacology·Qiyu QiuBertrand J Jean-Claude
Dec 24, 2002·Cancer Chemotherapy and Pharmacology·Stephanie L MathesonBertrand J Jean-Claude
Jul 11, 2003·Lancet·Janet E Dancey, Boris Freidlin
Sep 19, 2003·Journal of Medicinal Chemistry·Zakaria RachidBertrand J Jean-Claude
Sep 11, 2004·The Journal of Pharmacology and Experimental Therapeutics·Stephanie L MathesonBertrand J Jean-Claude

❮ Previous
Next ❯

Citations

Mar 30, 2010·The Journal of Pharmacology and Experimental Therapeutics·Ranjita BanerjeeBertrand J Jean-Claude
Jun 28, 2019·Current Pharmaceutical Design·Ana P FranciscoMaria J Perry
Mar 7, 2017·Future Medicinal Chemistry·Guohui SunRugang Zhong
Jan 26, 2011·Molecular Cancer Research : MCR·Ying HuangBertrand J Jean-Claude
Feb 19, 2008·Molecular Cancer Therapeutics·Andrea CavazzoniPier Giorgio Petronini

❮ Previous
Next ❯

Methods Mentioned

BETA
xenografts
protein assay
electrophoresis

Software Mentioned

Syngene GeneTools
ALKOMET

Related Concepts

Related Feeds

Carcinoma, Squamous Cell

Basal cell carcinoma is a form of malignant skin cancer found on the head and neck regions and has low rates of metastasis. Discover the latest research on basal cell carcinoma here.