Design and synthesis of new stabilized combi-triazenes for targeting solid tumors expressing the epidermal growth factor receptor (EGFR) or its closest homologue HER2

Rachid, Zakaria; MacPhee, Meaghan; Williams, Christopher; Todorova, Margarita; Jean‐Claude, Bertrand J.

doi:10.1016/j.bmcl.2009.05.060

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…Although numerous studies from our group have confirmed the dual actions of combi-molecules (7)(8)(9), little is known about the optimal condition under which they exhibit their optimal potency. With the purpose of increasing their stability, we recently reported in a stability optimization study, the synthesis of ZRS1 carrying an acetoxymethyl carbamate moiety that stabilizes the triazene moiety (11). Thus, for this study, we chose to test our hypothesis with ZRS1, a stable and water soluble combi-molecule.…”

Section: Discussionmentioning

confidence: 99%

“…One such molecule, ZRS1, contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazene-based DNA damaging one. Like its predecessors, under physiologic conditions, ZRS1 is designed to undergo hydrolysis to generate an aminoquinazoline FD105 (an EGFR inhibitor) and a methyl diazonium that damages DNA (11). The DNA methylating pharmacophore (3-methyl-1,2,3-triazene) of ZRS1 is similar to that of clinical chemotherapeutic methylating agents dacarbazine and temozolomide.…”

Section: Introductionmentioning

confidence: 99%

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MGMT Is a Molecular Determinant for Potency of the DNA-EGFR–Combi-Molecule ZRS1

Huang¹,

Rachid²,

Jean‐Claude³

2011

Molecular Cancer Research

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To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazenebased DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT). ZRS1 was more potent than the clinical methylating agent temozolomide in all cell lines, regardless of their MGMT status. However, its potency was in the same range as or less than that of Iressa, an EGFR inhibitor, against MGMT-proficient cells. In the MGMTdeficient or in MGMT-proficient cells exposed to the MGMT inhibitor O6-benzylguanine, its potency was superior to that of Iressa and temozolomide or a temozolomideþIressa combination. Cell signaling analysis in A549 (MGMT þ ) and A427 (MGMT -) showed that ZRS1 strongly inhibited EGFR phosphorylation and related signaling pathways. In addition, the p53 pathway was activated by DNA damage in both cell lines, but apoptosis was significantly more pronounced in A427 cells. Using MGMT shRNA to block endogenous MGMT protein expression in A549 resulted in significant sensitization to ZRS1. Furthermore, transfection of MGMT into A427 greatly decreased the potency of ZRS1. These results conclusively show that MGMT is a critical molecular determinant for the full-blown potency of the dual EGFR-DNA targeting combi-molecule. Mol Cancer Res; 9(3); 320-31. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MGMT Is a Molecular Determinant for Potency of the DNA-EGFR–Combi-Molecule ZRS1

Huang¹,

Rachid²,

Jean‐Claude³

2011

Molecular Cancer Research

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“…The EGFR selectivity of each agent was examined by comparing the IC 50 (50% inhibition constant) values for growth inhibition of the mouse NIH-3T3 fibroblast cell line with those of its EGFR transfectant NIH-3T3/HER-14. The chemistry of the stabilized combimolecules described herein was reported elsewhere [22,24].…”

Section: Introductionmentioning

confidence: 99%

“…This type of molecules RB24 [21,22] or RB107 [23] showed half-lives in the 45 minute range. With the purpose of enhancing the bioavailability of combi-molecules of the triazene class, we recently sought to further stabilize them by synthesizing a series of quinazoline-based 1,2,3-triazenes containing a hydrolabile carbamate at the 3-position of the triazene chain [24]. It was expected that the rate of hydrolysis of the triazene chain would control the stability of the molecules.…”

Section: Introductionmentioning

confidence: 99%

“…We recently developed a novel strategy termed "combitargeting" [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][26][27][28][29] that seeks to design molecules designated as "combi-molecules", capable of not only blocking the tyrosine kinase activity of EGFR, but also damaging the DNA of the cells, thereby conferring cytotoxic properties to these inhibitors. At the advanced stages, many solid tumours including breast, prostate and lung carcinomas overexpress EGFR, a receptor that in many cases activate the PI3K-Akt pathway, thereby leading to resistance to apoptosis [1,2].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain

et al. 2010

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Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation. Their half-lives were prolonged by ca 20-55 min when compared with their acetoxymethyltriazene counterparts. While they decomposed slowly in serum-containing medium, their intracellular decomposition was extremely rapid. They blocked EGFR tyrosine kinase in an isolated enzyme assay and in MDA-MB-468 breast cancer cells. Similarly, they all induced a dose-dependent DNA damage and G2/M cell cycle arrest in MDA-MB-468 cells, except the most stable compound ZRL2 (a 3-vinyl carbamate). ZRL4 (a chloromethyl carbamate) was the most potent and ZRL2 was the least active of the series against MDA-MB-468 cells. In selectivity assay with NIH-3T3 and NIH-3T3/HER-14, all compounds selectively blocked proliferation of NIH-3T3/HER-14. ZRS1 exerted the strongest growth inhibitory potency of the series. The results in toto suggest that ZRL2, despite being the most stable compound, could not hydrolyze at a rate that permitted the generation of DNA damaging species, thereby behaving primarily as an EGFR inhibitor. Thus the study permitted the definition of an optimized combi-molecule as one that decomposes at a rate that is slower than that of acetoxymethyltriazenes, but rapid enough to generate strong EGFR-DNA targeting potential and growth inhibition. Based on the latter criteria, ZRS1 and ZRL4 were tested in vivo and ZRS1 has proven the more effective.

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