Lead-oriented synthesis of epigenetic relevant scaffolds.

A simple and rational method to rank lead-likeness of molecules using continuous evaluation functions was hereby developed. This strategy proved to be competitive against known methods and finally helped in driving synthetic efforts towards candidates of interest for epigenetic applications against HDAC6, BRD4 and EZH2.

TAPBPR employs a ligand-independent docking mechanism to chaperone MR1 molecules.

Chaperones tapasin and transporter associated with antigen processing (TAP)-binding protein related (TAPBPR) associate with the major histocompatibility complex (MHC)-related protein 1 (MR1) to promote trafficking and cell surface expression. However, the binding mechanism and ligand dependency of MR1/chaperone interactions remain incompletely characterized. Here in vitro, biochemical and computational studies reveal that, unlike MHC-I, TAPBPR recognizes MR1 in a ligand-independent manner owing to the absence of major structural changes in the MR1 α helix between empty and ligand-loaded molecules.

Degradation of NSD3: What to Myc of it all?

Preventing uncontrolled gene expression is a powerful therapeutic strategy for the treatment of cancers. In this issue of Cell Chemical Biology, Xu et al. (2022) describe a series of proteolysis targeting chimeras that induce the degradation of NSD3 and suppress cMyc-related oncogene transcription in a model of acute myeloid leukemia.

Photochemical synthesis of an epigenetic focused tetrahydroquinoline library.

Discovery of epigenetic chemical probes is an important area of research with potential to deliver drugs for a multitude of diseases. However, commercially available libraries frequently used in drug discovery campaigns contain molecules that are focused on a narrow range of chemical space primarily driven by ease of synthesis and previously targeted enzyme classes (, kinases) resulting in low hit rates for epigenetic targets. Here we describe the design and synthesis of a compound collection that augments current screening collections by the inclusion of privileged isosteres for epigenetic targets.

Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres.

Epigenetic drug discovery provides a wealth of opportunities for the discovery of new therapeutics but has been hampered by low hit rates, frequent identification of false-positives, and poor synthetic tractability. A key reason for this is that few screening collections consider the unique requirements of epigenetic targets despite significant medicinal chemistry interest. Here we analyze the suitability of some commercially available screening collections in the context of epigenetic drug discovery, with a particular focus on lysine post-translational modifications, and show that even privileged motifs found in U.

Computational Mapping of Dirhodium(II) Catalysts.

The chemistry of dirhodium(II) catalysts is highly diverse, and can enable the synthesis of many different molecular classes. A tool to aid in catalyst selection, independent of mechanism and reactivity, would therefore be highly desirable. Here, we describe the development of a database for dirhodium(II) catalysts that is based on the principal component analysis of DFT-calculated parameters capturing their steric and electronic properties.

Activity-Directed Synthesis of Inhibitors of the p53/hDM2 Protein-Protein Interaction.

Protein-protein interactions (PPIs) provide a rich source of potential targets for drug discovery and biomedical science research. However, the identification of structural-diverse starting points for discovery of PPI inhibitors remains a significant challenge. Activity-directed synthesis (ADS), a function-driven discovery approach, was harnessed in the discovery of the p53/hDM2 PPI.

(C^N^C)Au complexes of acyclic carbene ligands: synthesis and anticancer properties.

A series of cyclometallated gold(iii) complexes supported by pyrazine-based (C^N^C)-type pincer ligands were synthesized via two different pathways. Nucleophilic attack on the isocyanide complex [(C^N^C)Au(C[triple bond, length as m-dash]NCHMe-2,6)]SbF (2) gave [(C^N^C)Au(ACC)]SbF complexes with aniline (4·SbF), adamantylamine (5), glycine ethyl ester (6), alanine methyl ester (7), valine methyl ester (8), phenylglycine methyl ester (9) and methionine methyl ester (10) substituents (ACC = acyclic carbene). The pathway via isocyanide insertion into gold-amide bonds was also investigated; e.

Keeping gay and bisexual men safe: The arena of HIV prevention science and praxis.

Abstract In this article, I draw from an ongoing ethnographic study of HIV prevention for gay, bisexual, and 'men who have sex with men' to develop an institutional analysis of HIV behavioral intervention science and praxis. I approach this analysis through the lens of the social worlds framework, focusing on the institutional arena in which HIV behavioral interventions are devised and executed. Toward this end, I focus on two fundamental points of contention that lie at the heart of the prevention enterprise and put its social organization in high relief: (1) conceptions of health and lifestyle practices and (2) attributions of expertise.

Health and sexual status in an urban gay enclave: an application of the stress process model.

In this article, I apply the stress process model as a framework to understand sexual sociality and its impact on health among urban gay men in a large North American gay enclave. Data consisting of in-depth interviews with 70 gay men coupled with three years of fieldwork demonstrate a sexual status order that privileges caucasian, middle-class men in their twenties and early thirties, and that disadvantages black and Asian men, men over 40 years of age, and poor men. Men with low sexual status faced significant stressors in the form of avoidance from others, stigmatization, and rejection.

Crystal methamphetamine and sexual sociality in an urban gay subculture: an elective affinity.

This paper draws on 49 qualitative interviews to explore the contextual antecedents of methamphetamine use in a sample of gay and bisexual Manhattan men. The paper distinguishes itself from the public health literature on crystal methamphetamine use in this population by shifting the analytic focus from individual-level factors of drug use to the role of social context. While individual-level factors--including self esteem and social awkwardness--are related to methamphetamine use, we argue that these factors arise in and are exacerbated by interactional pressures attendant to Manhattan's gay sexual subculture, which revolve around the expectation of peak sexual performance.