Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC₅₀ 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.

The current study presents the design, synthesis, and evaluation of novel cytochrome P450 17A1 (CYP17A1) ligands. CYP17A1 is a key enzyme in the steroidogenic pathway that produces androgens among other steroids, and it is implicated in prostate cancer. The obtained compounds are potent enzyme inhibitors (sub µM) with antiproliferative activity in prostate cancer cell lines. The binding mode of these compounds is also discussed.

Hormone‐sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet‐induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high‐fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild‐type mice. CBF was positively correlated with lectin‐stained vessel density. HSL deletion did not exacerbate HFD‐induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild‐type mice, and HSL deletion did not significantly aggravate HFD‐induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD‐induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet‐induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD‐induced neuroinflammation and memory dysfunction. image

Purpose: To evade immunosurveillance many cancers convert tryptophan (Trp) into kynurenine (Kyn), which induces immunotolerance and suppresses immune responses. Elevated Kyn amounts have been found in blood from patients with cutaneous melanoma. This study aimed to investigate whether higher Kyn abundance and lower Trp abundance can be detected on the surface of cutaneous melanoma lesions compared with adjacent non-lesional skin. Methods: Sixteen patients with suspected melanomas were enrolled in this study. All lesions were excised and histopathologically diagnosed: 7 lesions were diagnosed as invasive malignant melanomas (MM), 6 as melanomas in situ (MIS), and 3 as benign lesions (BL). Non-invasive metabolite sampling was performed by tape stripping of suspected skin lesions and adjacent healthy non-lesional (NL) skin. Trp, Kyn, tyrosine (Tyr), and phenylalanine (Phe) were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Electrical impedance spectroscopy (EIS) measurements were conducted to assess skin barrier integrity. Results: Levels of all metabolites, Tyr (x6), Phe (x6), Trp (x5), and Kyn (x3), were significantly higher in MM lesions compared with adjacent NL skin, resulting in an elevated Trp/Kyn ratio. Trp levels increased less than Phe and Tyr levels, suggesting a potential increase in Trp depletion. Skin resistance in MM lesions was half that of NL skin. No differences were observed between MIS or BL and NL skin. Conclusions: Non-invasive skin sampling revealed elevated Tyr, Phe, Trp and Kyn levels in MM skin, which is likely the result of compromised skin barrier at this stage of cutaneous melanoma.

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN -amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change toward an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.