RESUMEN
While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.
RESUMEN
Draft genomes of two strains of Escherichia coli, FP2 and FP3, isolated from the feces of the Canada goose (Branta canadensis), were sequenced. Genome sizes were 5.26 Mb with a predicted G+C content of 50.54% (FP2) and 5.07 Mb with a predicted G+C content of 50.41% (FP3).
RESUMEN
As part of their curriculum, senior dental hygiene students at Dalhousie University Faculty of Dentistry provide tobacco cessation counseling (TCC). This study was conducted to evaluate the effectiveness of the TCC didactic curriculum and its clinical extensions. Research methods included a comprehensive literature search, an assessment of available resources related to TCC, and a structured telephone interview. The interview, consisting of ten summative questions, was conducted to determine the current tobacco use status of clients who had been counseled by a dental hygiene student for tobacco cessation. A target population of 132 subjects was extracted from axiUm, Dalhousie University dental clinic's patient database. The population represented clients who had TCC from 2001 to 2008. The investigators wanted to know if the client was 1) advised to quit tobacco use; 2) informed of the health risks of using tobacco; 3) still using tobacco; 4) taught self-examination techniques for oral cancer; and 5) if any post-counseling follow-up was initiated. A convenience size of fifty-one subjects was obtained. Survey results, along with the assessment of resources, revealed that the current TCC program needed improvement. As a result of the research, changes were implemented aimed at improving the effectiveness of the TCC program, and recommendations were made for further changes to enhance the overall program effectiveness.