Drug development and potential targets for Cushing's syndrome.

Cushing's syndrome (CS) is a complex disorder characterized by the excessive secretion of cortisol, with Cushing's disease (CD), particularly associated with pituitary tumors, exhibiting heightened morbidity and mortality. Although transsphenoidal pituitary surgery (TSS) stands as the primary treatment for CD, there is a crucial need to optimize patient prognosis. Current medical therapy serves as an adjunctive measure due to its unsatisfactory efficacy and unpredictable side effects. In this comprehensive review, we delve into recent advances in understanding the pathogenesis of CS and explore therapeutic options by conducting a critical analysis of potential drug targets and candidates. Additionally, we provide an overview of the design strategy employed in previously reported candidates, along with a summary of structure-activity relationship (SAR) analyses and their biological efficacy. This review aims to contribute valuable insights to the evolving landscape of CS research, shedding light on potential avenues for therapeutic development.

Discovery of Novel Aminobutanoic Acid-Based ASCT2 Inhibitors for the Treatment of Non-Small-Cell Lung Cancer.

Alanine-serine-cysteine transporter 2 (ASCT2) is up-regulated in lung cancers, and inhibiting it could potentially lead to nutrient deprivation, making it a viable strategy for cancer treatment. In this study, we present a series of ASCT2 inhibitors based on aminobutanoic acids, which exhibit potent inhibitory activity. Two compounds, 20k and 25e, were identified as novel and potent ASCT2 inhibitors, with IC50 values at the micromolar level in both A549 and HEK293 cells, effectively blocking glutamine (Gln) uptake. Additionally, these compounds regulated amino acid metabolism, suppressed mTOR signaling, inhibited non-small-cell lung cancer (NSCLC) growth, and induced apoptosis. In vivo, experiments showed that 20k and 25e suppressed tumor growth in an A549 xenograft model, with tumor growth inhibition (TGI) values of 65 and 70% at 25 mg/kg, respectively, while V9302 only achieved a TGI value of 29%. Furthermore, both compounds demonstrated promising therapeutic potential in patient-derived organoids. Therefore, these ASCT2 inhibitors based on aminobutanoic acids are promising therapeutic agents for treating NSCLC by targeting cancer Gln metabolism.

Design strategies and recent development of bioactive modulators for glutamine transporters.

Glutamine transporters are integral to the metabolism of glutamine in both healthy tissues and cancerous cells, playing a pivotal role in maintaining amino acid balance, synthesizing biomolecules, and regulating redox equilibrium. Their critical functions in cellular metabolism make them promising targets for oncological therapies. Recent years have witnessed substantial progress in the field of glutamine transporters, marked by breakthroughs in understanding of their protein structures and the discovery of novel inhibitors, prodrugs, and radiotracers. This review provides a comprehensive update on the latest advancements in modulators targeting the glutamine transporter, with special attention given to LAT1 and ASCT2. It also discusses innovative approaches in drug design aimed at these transporters.

Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy.

CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate cancer therapy.

An updated patent review of glutaminase inhibitors (2019-2022).

INTRODUCTION: Kidney-type glutaminase (GLS1), a key enzyme controlling the hydrolysis of glutamine to glutamate to resolve the 'glutamine addiction' of cancer cells, has been shown to play a central role in supporting cancer growth and proliferation. Therefore, the inhibition of GLS1 as a novel cancer treating strategy is of great interest. AREAS COVERED: This review covers recent patents (2019-present) involving GLS1 inhibitors, which are mostly focused on their chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications. EXPERT OPINION: Currently, despite significant efforts, the search for potent GLS1 inhibitors has not resulted in the development of compounds for therapeutic applications. Most recent patents and literature focus on GLS1 inhibitors IPN60090 and DRP104, which have entered clinical trials. While other patent disclosures during this period have not generated any drug candidates, the clinical update will inform the potential of these inhibitors as promising therapeutic agents either as single or as combination interventions.