Neuronal Kv7 channels represent important pharmacological targets for hyperexcitability disorders including epilepsy. Retigabine is the prototype Kv7 activator clinically approved for seizure treatment; however, severe side effects associated with long-term use have led to its market discontinuation. Building upon the recently described cryoEM structure of Kv7.2 complexed with retigabine and on previous

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting about 145 million people worldwide. Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. Herein, we describe the discovery of a series of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines

Protein flexibility is important for ligand binding but often ignored in drug design. Considering proteins as ensembles rather than static snapshots creates opportunities to target dynamic proteins that lack FDA-approved drugs, such as the human chaperone, heat shock protein 90 (Hsp90). Hsp90α accommodates ligands with a dynamic lid domain, yet no comprehensive analysis relating lid conformations to

Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions and thus be functionally similar. Using three-dimensional structures of many fragments bound to multiple targets, we examined if a better strategy for selecting fragments for

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2)

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate

Pages 11611 and 11612, references 18 and 42 should be switched, such that ref 18, cited on page 11598, refers to the work by Sorrenti et al., and ref 42, cited on page 11599, refers to the work by Amata et al. Page 11599. A new reference (cited here as ref (1)) should be added at the end of the first sentence of the last paragraph of the Introduction: “...endowed with a 4-nitro-3-trifluoromethylaniline

Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL

High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks

Aberrant regulation of N6-methyladenosine (m6A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m6A demethylase fat mass- and obesity-associated protein (FTO), which removes both m6A and N6,2′-O-dimethyladenosine (m6Am) RNA modifications. In this work, we describe the rational design and optimization

Melatonin is a neurohormone released in a circadian manner with peak levels at night. Melatonin mediates its effects mainly through G protein-coupled MT1 and MT2 receptors. Drugs acting on melatonin receptors are indicated for circadian rhythm- and sleep-related disorders. Tools to study the activation of these receptors with high temporal resolution are lacking. Here, we synthesized a family of light-activatable

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2–9 in 77–99%

High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide–alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus

The δC value for carbon 4′ of compound 10 was incorrect, and one of the funding sources (and associated grant proposal code) was omitted. Therefore, we provide here a correct value for the δC-4′ (19.4 ppm) in a corrected version of Table 1. We also provide the missing funding source and grant number. 1H NMR (600 MHz, CD3OD). 13C NMR (151 MHz, CD3OD). 1H NMR (500 MHz, CD3OD). 13C NMR (126 MHz, CD3OD)

The effect of polypyridyl Ru(II) complexes on the ability of cancer cells to migrate and invade, two features important in the formation of metastases, is evaluated. In vitro studies are carried out on breast cancer cell lines, MDA-MB-231 and MCF-7, as well as melanoma cell lines A2058 and A375. Three Ru(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and as a third ligand

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound