An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.     

Plastic Degradation by Extremophilic Bacteria

Intensive exploitation, poor recycling, low repeatable use, and unusual resistance of plastics to environmental and microbiological action result in accumulation of huge waste amounts in terrestrial and marine environments, causing enormous hazard for human and animal life. In the last decades, much scientific interest has been focused on plastic biodegradation. Due to the comparatively short evolutionary period of their appearance in nature, sufficiently effective enzymes for their biodegradation are not available. Plastics are designed for use in conditions typical for human activity, and their physicochemical properties roughly change at extreme environmental parameters like low temperatures, salt, or low or high pH that are typical for the life of extremophilic microorganisms and the activity of their enzymes. This review represents a first attempt to summarize the extraordinarily limited information on biodegradation of conventional synthetic plastics by thermophilic, alkaliphilic, halophilic, and psychrophilic bacteria in natural environments and laboratory conditions. Most of the available data was reported in the last several years and concerns moderate extremophiles. Two main questions are highlighted in it: which extremophilic bacteria and their enzymes are reported to be involved in the degradation of different synthetic plastics, and what could be the impact of extremophiles in future technologies for resolving of pollution problems.     

Contribution of Microcosm and Respirometric Experiments to PAHs' Intrinsic Biodegradation in the Soil of a Former Coke Site

Microcosm and respirometric experiments were used to evaluate polycyclic aromatic hydrocarbons' (PAHs') intrinsic biodegradation in soil from a former coke site. The study was carried out in solid phase, over 12 months, at 20°C, in aerobic conditions. Microbial degradation activity in respirometry was assessed by monitoring the CO₂ production and O₂ consumption as well as by following the decrease in PAH content in the soil samples. PAHs' biodegradation patterns are very similar both in microcosm experiments and in respirometry. Respirometric experiments show CO₂ production and O₂ consumption over all biodegradation experiments, whereas no more loss of PAHs is measured after only a few weeks of experimentation. This indicates that monitoring only CO₂ production or O₂ consumption is not enough to assess PAHs' biodegradation. It seems that, after having degraded the most available PAHs, microbiota shift to other sources of carbon for their metabolism.     

Constitutively Active Androgen Receptor in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression.     

CHARACTERISTICS OF PAHS INTRINSIC DEGRADATION IN TWO COKE FACTORY SOILS

Polycyclic aromatic hydrocarbons (PAHs) are the most commonly found pollutants in former coke site grounds. These organic pollutants are particularly a concern because of their possible toxic, carcinogenic or mutagenic properties. Biodegradation is one possible pathway for PAHs elimination from soils. This study aims to evaluate intrinsic degradation potential of PAHs in soils taken from two former coke sites, differing by their contamination levels and by their physico-chemical characteristics (organic carbon and metal contents).PAHs biodegradation kinetics as observed in both soil types distinguishes between two steps: a first step showing a rapid but short PAHs abiotic degradation, followed by a second step which is characterized by a much slower PAHs decrease pattern, progressively smoothing along time. These patterns lead to a significant decrease in the bulk PAHs content of 35% and 46% respectively for site 1 and site 2 soils after 12 months. In this experiment, PAHs degradation seems to be altered neither by the conditions of the medium (availability of carbon, phosphorus, nitrogen, moisture, oxygen …), nor by any decrease in bacterial degrading activity, but rather by lack of PAHs' bioavailability and recalcitrance of some degradation products. If the occurrence of metals and organic carbon does not alter the bulk yield of PAHs' degradation, it does modify the degradation pattern, insofar as bacterial processes seem to need longer to set when metals and organic carbon are present in higher amounts.     

Stopping powers of gases for 40 MeV/u tellurium ions

The stopping powers of six gaseous media have been measured for incident 40 MeV/u ¹²⁵Te heavy ions. The energy losses of ions in various “thicknesses” of gas have been accurately determined. The gases were confined in a cell. The amount of matter traversed by the ions was determined from temperature and pressure measurements. The beam energy before and after slowing down were measured using the LISE magnetic spectrometer at GANIL. These experimental gas stopping powers are lower by about 10% than the corresponding tabulated values for solid media. This means that the gas–solid effect is still significant at 40 MeV/u for Te ions. The projectile effective charges derived from these measurements depend on the target atomic number, thus confirming the trend observed in previous experiments performed with lighter ions or at lower energies.     

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degrader-induced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern drug-induced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.     

Front Cover: Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity (ChemBioChem 19/2023)

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation.