In 2007, FDA-approved lapatinib in combination therapy for treatment of HER2 positive breast cancer. However, its effectiveness is limited by resistance that frequently emerges following treatment. T790M/L858R resistance is the most commonly reported EGFR-resistance and accounting for 60-60% of the acquired resistance. Inspired by this fact, we tackled T790M/L858R resistance through design, synthesis of 27 novel 4,6 disubstituted quiazoline derivatives with more structural flexibility at the solvent accessible region to avoid the steric clashes of the mutant M790. This design was conducted through multistep reactions to incorporate different flexible spacer at position 6 of quinazoline ring, namely, (propoxy, acetamide or methylbenzamide), this followed by nucleophilic substitution with several polar fragments. At position 4, “N-(4-(3-chloro-4-(3-fluorobenzyl)oxy)phenyl)amino” fragment of lapatinib was replaced by “N-(4-(3-chloro-4-(3-substituted-phenoxy)phenyl)amino)” moiety to fit into the lipophilic back pocket with an enhanced selectivity against the target HER-2 kinase enzyme. Protein kinase profiling at 10 µM single measurements, using a radioactive assay method with [γ-33P]ATP was conducted for 7 compounds using lapatinib as a reference standard. The profiling data for compounds 12f, 23a, 23e, 23L,18a, 18c, 25d, gave similar profiles with strong inhibitions ranging from (-90.9% to -93.4%] against the target HER-2 kinase, whereas lapatinib demonstrated an inferior inhibition (-52%). In addition, these compounds revealed significant reduction of ABL, EGFR, HER4 and JAK2 compared to the control values. Remarkably, the screened compounds exhibited insignificant activation or even mild inhibition of other kinases which are activated by lapatinib, anticipating lower side effects and toxicity of our designed compounds compared to lapatinib. NCI-60 cell lines single dose screening at 10-5 M was applied for 10 compounds, 5 compounds exhibited potent and wide spectrum of growth inhibition and were selected for 5 doses assay. In addition, the preliminary MTT assay in AU565 cells (HER2 +ve breast cancer cell line) revealed promising IC50 values, 0.35 µM, 0.6 µM, 0.88 µM, 0.56 µM, 0.64 µM and 0.55 µM for compounds, 25c, 23a, 23d, 23b, 23e and 23g, respectively.

HER-2 kinase-targeted cancer therapy: Design, synthesis, and kinase profiling of novel quinazoline derivatives as selective antitumor hits

2019 Fall National Meeting

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