Prostate cancer (PCa) therapy typically involves administration of “classical” antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full (“true”) antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

Abstract

Objective: This review examines on our current understanding of microbial lipase solvent tolerance, with a specific focus on the molecular strategies employed to improve lipase stability in a non-aqueous environment. Results: It provides an overview of known solvent tolerant lipases and of approaches to improving solvent stability such as; enhancing stabilising interactions, modification of residue flexibility and surface charge alteration. It shows that judicious selection of lipase source supplemented by appropriate enzyme stabilisation, can lead to a wide application spectrum for lipases. Conclusion: Organic solvent stable lipases are, and will continue to be, versatile and adaptable biocatalytic workhorses commonly employed for industrial applications in the food, pharmaceutical and green manufacturing industries.

The disadvantage to students of beginning a module with no prior knowledge or inaccurate knowledge is well documented. For learners, the development of the necessary prior knowledge to facilitate their learning is essential. The use of screencasts, whether prior to or during class, is becoming more widespread. There is a need, however, to better understand how these are used and whether or not there is any impact on overall learner engagement and academic achievement when a component with instantaneous feedback (such as a multiple choice quiz) is embedded into the pre-lecture screencast activity. In this study, pre-learning activities consisting of screencasts and multiple choice quizzes were introduced to improve student engagement with the topic, gauge common misconceptions and give timely feedback to the students. An examination of screencast usage indicated that students did not predominantly nor exclusively employ the resources as originally intended, that is, in advance of lectures. Rather, students continued to access the activities across the module and often after the associated lecture. Implications are discussed with an acknowledgement of the importance of taking into account how learners prefer to use resources when designing and introducing new activities to modules.

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.