JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing.
Mol. Cancer Ther.
PUBLISHED: 04-10-2014
Show Abstract
Hide Abstract
Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR(WT)). These inhibitors have not provided compelling clinical benefit in T790M-positive patients, apparently because of dose-limiting toxicities associated with inhibition of EGFR(WT). Thus, there is an urgent clinical need for therapeutics that overcome T790M drug resistance while sparing EGFR(WT). Here, we describe a lead optimization program that led to the discovery of four potent irreversible 2,4-diaminopyrimidine compounds that are EGFR mutant (EGFR(mut)) selective and have been designed to have low affinity for EGFR(WT). Pharmacokinetic and pharmacodynamic studies in H1975 tumor-bearing mice showed that exposure was dose proportional resulting in dose-dependent EGFR modulation. Importantly, evaluation of normal lung tissue from the same animals showed no inhibition of EGFR(WT). Of all the compounds tested, compound 3 displayed the best efficacy in EGFR(L858R/T790M)-driven tumors. Compound 3, now renamed CO-1686, is currently in a phase I/II clinical trial in patients with EGFR(mut)-advanced NSCLC that have received prior EGFR-directed therapy.
Related JoVE Video
Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC.
Cancer Discov
PUBLISHED: 09-24-2013
Show Abstract
Hide Abstract
Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
Related JoVE Video
Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3K?.
J. Med. Chem.
PUBLISHED: 02-05-2013
Show Abstract
Hide Abstract
PI3K? has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3K?. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3K? on cysteine 862 (C862), an amino acid unique to the ? isoform, and that PI3K?, -?, and -? are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3K?-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3K?, was used to investigate the duration of occupancy of 3 with PI3K? in vivo. This is the first report of a PI3K?-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3K?.
Related JoVE Video
Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine.
Nat. Chem. Biol.
PUBLISHED: 08-17-2010
Show Abstract
Hide Abstract
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.