ACS Medicinal Chemistry Letters最新文献

RNAs are increasingly considered valuable therapeutic targets, and the development of methods to identify and validate both RNA targets and ligands is more important than ever. Here, we utilized a bioinformatic approach to identify a hairpin-containing RNA G-quadruplex (rG4) in the 5′ untranslated region (5′ UTR) of DHX15 mRNA. By using a novel competitive small molecule microarray (SMM) approach, we identified a compound that specifically binds to the DHX15 rG4 (K_D = 12.6 ± 1.0 μM). This rG4 directly impacts translation of a DHX15 reporter mRNA in vitro, and binding of our compound (F1) to the structure inhibits translation up to 57% (IC₅₀ = 22.9 ± 3.8 μM). This methodology allowed us to identify and target the mRNA of a cancer-relevant helicase with no known inhibitors. Our target identification method and the novelty of our screening approach make our work informative for future development of novel small molecule cancer therapeutics for RNA targets.

Provided herein are novel 2,7-naphthyridine compounds as MASTL inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Cryptococcal neoformans and Candida albicans are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (4377), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of 4377. All four stereoisomers retain potent antifungal activity with the erythro enantiomers having MIC values of 1 and 4 μg/mL against C. neoformans and C. albicans, respectively, and threo enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of 4377 and gives guidance to future medicinal chemistry optimization efforts.

Herein, we describe the design, synthesis, and in vitro biological evaluation of HO-1 inducers endowed with cytotoxic effects mediated by ferroptosis activation. Using the natural HO-1 inducer caffeic acid phenethyl ester (CAPE) as a chemical scaffold, new derivatives were synthesized by performing modifications in the cathecol moiety and in the phenethyl ester aromatic ring. Biological assays aimed at evaluating an imbalanced activity of ferroptosis key players identified that 2-(1H-indol-3-yl)ethyl cinnamate (compound 24) possesses improved anticancer activity toward the MDA-MB 231 triple negative breast cancer cell line when compared to CAPE. Increased ROS and LOOH levels, reduced GSH levels, imbalanced mitochondrial activity, and restored cell viability after ferrostatin-1 treatment suggested a ferroptotic mechanism of action, which did not involve GPX4 inhibition. Compound 24 represents an intriguing hit compound useful for the identification of novel ferroptosis inducers.

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure–activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been identified as a promising oncogenic driver of several types of cancer and is considered to be a critical cancer therapeutic target. Several inhibitors of DYRK2 have been reported, but no degraders have been found yet. In this work, we designed and synthesized the first series of proteolysis-targeting chimeras (PROTACs) using curcumin and its analogs as warheads to target and degrade DYRK2. The results of degradation assays showed that the compound CP134 could effectively downregulate the intracellular DYRK2 level (DC₅₀ = 1.607 μM). Further mechanism of action experiments revealed that CP134 induced DYRK2 degradation through the ubiquitin–proteasome system. Altogether, CP134 disclosed in this study is the first potent DYRK2 degrader, which could serve as a valuable chemical tool for further evaluation of its therapeutic potential, and our results broaden the substrate spectrum of PROTAC-based degraders for further therapeutic applications.

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

Targeted protein degradation (TPD) technologies represent a groundbreaking approach in cancer therapy, focusing on the selective degradation of oncogenic proteins such as BCL6 and SMARCA2. By leveraging the ubiquitin-proteasome system, TPD offers a novel strategy that surpasses traditional therapies’ limitations, targeting the core mechanisms of oncogenesis. This article explores the significant advancements in TPD, detailing innovative strategies for the degradation of essential proteins implicated in cancer, and discusses the potential of these approaches to transform cancer treatment through precision medicine and personalized therapy.

This Patent Highlight delves into the ground-breaking impact of Proteolysis Targeting Chimeras (PROTACs) on targeted protein degradation, offering novel strategies to eliminate pathogenic proteins. By exploring the cutting-edge development of compounds targeting IRAK-4 and CDK2, this work illuminates PROTACs’ role in treating immune disorders and cancer. The analysis not only highlights the specificity and potential of PROTACs in transforming disease treatment but also addresses the challenges and future directions of this technology, emphasizing its broad applicability and the promise of more effective therapeutic strategies.