Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant.

The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties.

Taking into consideration the biological activity of the only natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were synthesized starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)aniline (1) in two steps by isolating the intermediates 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) and (Z)-4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobut-2-enoic acid (6). The two natural product analogs 4 and 7 were then tested for antitumor activity toward a panel of 11 cell lines in vitro by using a monolayer cell-survival and proliferation assay. Compound 7 was the most potent and exhibited a mean IC50 value of approximately 9.4 µM. Aniline 1 was synthesized by two routes in one-pot reactions starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography.

The preclinical and clinical activity of aviscumine: a potential anticancer drug.

Extracts from the European mistletoe plant Viscumalbum have been studied for decades for their direct and indirect anticancer activity. Therefore, scientists were interested in identifying the active compound (mistletoe lectin) in these extracts and making it available as a highly purified molecule for drug development. Recombinant mistletoe lectin (INN: aviscumine) was produced in Escherichiacoli. It has been shown to have immunomodulatory and cytotoxic activity in invitro and in animal models and can target tumour cells. Clinical phase I studies also demonstrated immunomodulatory activity, which appears to have a positive effect on disease stabilisation. This review explores the current knowledge base for aviscumine's mechanism of action, efficacy and side-effects in both preclinical studies and clinical trials, and it considers aviscumine's potential as a cancer therapy.