RSC medicinal chemistry最新文献

Fv-antibodies targeting the transmembrane protease serine 2 (TMPRSS2) were screened from an Fv-antibody library for inhibiting SARS-CoV-2 infection. Fv-antibodies were derived from the variable region of heavy-chain immunoglobulin G (IgG), which consisted of three complementarity-determining regions (CDRs) and frame regions (FRs). The Fv-antibody library was prepared through site-directed mutagenesis of CDR3 region. The proteolytic cleavage site (S2' site) of TMPRSS2 on the spike protein (SP) of SARS-CoV-2 was used as a screening probe for the library. Two Fv-antibodies were screened and subsequently expressed as soluble recombinant proteins. The binding affinities of the expressed Fv-antibodies were estimated using a surface plasmon resonance (SPR) biosensor. The two expressed Fv-antibodies specifically bound to the active site of TMPRSS2 which interacts with S2' site in the proprotein convertase (PPC) region. The neutralizing activities of the two expressed Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses that expressed the SP of four types of SARS-CoV-2 variants: Wu-1 (D614), Delta (B.1.617.2), Omicron (BA.2), and Omicron (BA.4/5). Additionally, a docking simulation was performed to analyze the interaction between the screened Fv-antibodies and the active sites of TMPRSS2.

Alzheimer's disease (AD) stands as one of the most outstanding progressive neurodegenerative disorders. Obviously, acetylcholine esterase (AChE) is the primary enzyme responsible for breaking down acetylcholine (ACh) with a much more prominent effect than butyrylcholine esterase (BuChE). Hence, novel quinazoline derivatives (3a-p) were designed and synthesized as AChE inhibitors for AD treatment. The newly synthesized quinazoline derivatives (3a-p) were pursued for their inhibitory potential towards both AChE and BuChE. Notably, compound 3e displayed the highest inhibitory potential towards AChE (IC₅₀ = 9.26 nM) surpassing donepezil (IC₅₀ = 16.43 nM). On the other side, compound 3e effectively negated the decline in memory acquisition and retention instigated by ICV administration of streptozotocin (STZ) in mice, an effect that was comparable to that produced by donepezil. Moreover, compound 3e, reduced BACE1 by 51.08% (p < 0.0001), Aβ42 by 52.47% (p < 0.0001), and p(Ser199)-tau by 69.16% (p < 0.0001) compared to STZ mice. Such effects were similar to those of donepezil which reduced all 3 parameters by 57.53%, 58.5%, and 66.78%, respectively, compared to STZ mice. Furthermore, molecular docking studies showed that the superimposition view clarified the similar binding mode of both 3e and the co-crystallized donepezil at the AChE binding pocket. Moreover, the docked complexes (3e-AChE and 3e-BuChE) were further subject to molecular dynamics simulations for 100 ns. In addition, eligible pharmacokinetic profiles as well as feasible BBB penetration were anticipated for compound 3e using ADME and BBB permeation prediction studies. Accordingly, the synthesized compounds, in particular compound 3e, can be treated as promising lead compounds for AD treatment with future further optimization.

Although it is possible to discover new drug candidate molecules using in silico approaches, chemical synthesis followed by screening of their functions is still at the center of bioactive molecule discovery. While determining the potential effects of compounds on target signaling molecules or pathways, assessing their effects on the circadian rhythm is also very important for determining the efficacy of drug candidates because they control most of the signaling pathways. Herein, new members of the biocompatible cyclotriphosphazene family were prepared, and their in vitro biological activities and effects on circadian rhythm were evaluated for the first time. In particular, new cyclotriphosphazene derivatives carrying morpholine, thiomorpholine and triazole groups were designed and synthesized, and their chemical structures were characterized using appropriate spectroscopic methods. Cellular toxicity analyses of the compounds were performed using different biological methods, such as determination of IC₅₀ values, calculation of population doubling times, and colony formation patterns. Subsequently, the effects of the compounds on the cell cycle were analyzed using the flow cytometry technique. Finally, the effects of the synthesized compounds on circadian rhythm were determined using a real-time bioluminescence approach. Based on these studies, it was determined that some compounds demonstrated varying degrees of antiproliferative activity, with the most potent compounds causing G₂/M phase arrest. Additionally, most derivatives had no adverse effects on the circadian rhythm, indicating their potential for safe therapeutic application in targeting cell proliferation. Furthermore, an important pharmacological characteristic of the drug candidate molecules, namely, membrane permeability in terms of log P values, was assessed. In conclusion, these novel cyclotriphosphazene-based compounds are a class of circadian rhythm-safe drug candidate compounds.

The ubiquitin proteasome system (UPS) has been successfully hi-jacked by both bifunctional and monovalent small molecules to affect the degradation of proteins that were once considered undruggable. This field has primarily focused on the targeted recruitment of proteins to substrate receptors on E3 ubiquitin ligases, which are only one part of the UPS. More recently, the field has begun to explore recruitment to other types of UPS proteins including E2 ubiquitin-conjugating enzymes, substrate adaptor proteins within the E3 complex, chaperone proteins that associate with E3s, proteasomal subunits, and proteasome-associated proteins. While these approaches are relatively nascent compared to more traditional E3 substrate receptor-based degradation, these approaches are starting to show promise and could offer unique advantages. This review will cover key findings in small molecule UPS-mediated targeted protein degradation (TPD) affected by co-opting proteins beyond traditional E3 substrate receptors.

Leucine-rich α-2 glycoprotein 1 (LRG1) is a secreted glycoprotein implicated in various diseases, yet its role across multiple cancers remains insufficiently explored. Consequently, we conducted a comprehensive bioinformatics analysis, exploring LRG1 expression patterns, prognostic implications, and potential therapeutic associations in a pan-cancer context. Additionally, we collected gene expression and clinical data from patients with kidney renal clear cell carcinoma (KIRC) from TCGA, conducting gene set enrichment analysis (GSEA) and Cox proportional hazards regression analysis to explore the potential regulatory role of LRG1 in KIRC. Our study revealed that LRG1 expression is upregulated in 18 cancer types, with elevated levels correlating with poor prognostic outcomes in several cancers, notably KIRC. Epigenetic analysis showed hypomethylation in the LRG1 promoter region, potentially contributing to the overexpression of LRG1. Moreover, LRG1 expression was linked to immunotherapeutic responses and altered drug sensitivities, particularly influencing the efficacy of tyrosine kinase inhibitors. In KIRC, high LRG1 expression was associated with the activation of key pathways, including angiogenesis, epithelial-mesenchymal transition (EMT), and hypoxia signalling. We identified key gene pairs interacting with LRG1 in KIRC, including CARD14 and CYP8B1, with CARD14 overexpression correlating with poorer clinical outcomes and CYP8B1 indicating a favourable prognosis. In conclusion, LRG1 emerges as a potential biomarker for prognosis and immunotherapy responsiveness in both pan-cancer and KIRC contexts. This study provides a theoretical foundation for further research on the therapeutic potential of target regulating LRG1 in cancer treatment.

The stimulator of interferon genes (STING) has been an attractive target in cancer immunotherapy. However, natural ligand cyclic dinucleotides (CDNs) and CDN derivatives have demonstrated limited efficacy in clinical trials. This limitation stems from the inherent structure of CDNs, which leads to enzymatic degradation, poor cell internalisation, rapid clearance from the tumour microenvironment, and dose-limiting toxicity. In this study, we developed an amphipathic STING agonist, termed albumin-binding CDNs (AlbiCDNs), to enhance the efficacy of c-di-GMP (CDG) via a lipid-conjugated strategy. The lipid provided a platform for albumin hitchhiking, which facilitated the cytoplasmic delivery of CDG without the use of any exogenous components. In addition, incorporating a stimuli-responsive lipid motif further enhanced the cellular release of CDG. Our results indicated that CDG-1C14, an AlbiCDN, efficiently stimulated the maturation and activation of antigen-presenting cells through STING activation. Furthermore, CDG-1C14 exhibited a significant inhibitory effect on the tumour therapeutic model. Therefore, AlbiCDN is a potent platform for cancer immunotherapy that can expedite clinical translation.

PROteolysis TArgeting Chimeras (PROTACs), also known as ligand-directed degraders (LDDs), are an innovative class of small molecules that leverage the ubiquitin-proteasome system to induce the degradation of target proteins. Structure based design methods are not readily applicable for designing LDDs due to the dynamic nature of the ternary complexes. This study investigates the dynamic properties of five LDD-mediated BRD4-cereblon complexes, focusing on the challenges of evaluating linker efficiency due to the difficulty in identifying suitable computational metrics that correlate well with the cooperativity or degradation propensity of LDDs. We uncovered that protein frustration, a concept originally developed to understand protein folding, calculated for the residues in the protein-protein interface of the LDD-mediated ternary complexes recapitulate the strength of degradation of the LDDs. Our findings indicated that hydrophobic residues in the interface are among the highly frustrated residues pairs, and they are crucial in distinguishing strong degraders from weak ones. By analyzing frustration patterns, we identified key residues and interactions critical to the effectiveness of the ternary complex. These insights provide practical guidelines for designing and prioritizing more efficient degraders, paving the way for the development of next-generation LDDs with improved therapeutic potential.

Protein-protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular networks. However, targeting a specific PPI of the hub protein 14-3-3, with its plethora of potential client proteins, poses a significant selectivity challenge. This not only involves the selectivity of 14-3-3 PPIs with other client proteins, but also the selective stabilization of a specific 14-3-3 binding site within a protein partner featuring several binding sites. The interaction of 14-3-3 with Tau, characterized by different phospho-site driven binding modes, forms a valuable, disease-relevant, 14-3-3 multivalent model PPI to explore this selectivity issue. This work presents the identification and early-stage optimization of small molecule fragment-like stabilizers for a specific binding site of the 14-3-3/Tau PPI. Using different biophysical assays, the stabilizing potency of the imine-bond forming molecules was mapped and X-ray crystallography studies provided structural data on the binding mode of the ternary complexes. Exploiting the unique topologies and functionalities of the different binding sites enabled the engineering of selectivity for this initial molecular glue matter for the pS214 binding site, over a second 14-3-3 binding site in Tau (pS324). These reversible covalent tool compounds will allow for the further exploration of the role of 14-3-3 in Tau aggregation.

NF-κB inducing kinase (NIK) is the central regulatory component of noncanonical NF-κB signalling and has been implicated in a variety of cancers and immune disorders. While NIK has been pursued as a target for such diseases through the design of orthosteric inhibitors, these inhibitors have not resulted in an approved drug. To develop new modalities for NIK-targeting by small molecules, we recently reported a class of chromanol fragments that bind to an unknown allosteric site on the catalytic domain of NIK. Here we report the design of a covalent probe to identify the location of this allosteric binding site. Acrylamide probe 2 (K _d: 24.5 μM) was determined to specifically adduct C573 out of 11 total cysteines on the catalytic domain of NIK, thereby identifying the allosteric binding site of our developed ligands.

Herein, we report the synthesis of 16 tubastatin A derivatives with fluorinated bi-, tri-, and tetracyclic cap groups. Most derivatives show strong in vitro antitumor activity, achieving micromolar or sub-micromolar efficacy. The most promising compound, 4-(6-bromo-3,3-difluoro-1,2,3,4-tetrahydro-9H-carbozol-9-yl)methyl)-N-hydroxybenzamide (14f), demonstrated potent anti-proliferative effects against human nasopharyngeal carcinoma cells (SUNE1) and human breast cancer cells (MDA-MB-231), with IC₅₀ values of 0.51 μM and 0.52 μM, respectively. Notably, compound 4-((8-fluoroindeno[2,1-b]indol-5(6H)-yl)-N-hydroxybenzamide (13c) exhibited significant anti-proliferative activity against pancreatic cancer cells (SW1990), with an IC₅₀ of 2.06 μM and low cytotoxicity to normal cells. Overall, variations in the cap group from bi- to tri-, then to tetracyclic, and the introduction of fluorinated groups enhance the antitumor activity of these derivatives. Among them, difluoromethyl-modified tricyclic derivatives show a broad spectrum in vitro antitumor effect. Molecular docking studies indicate that these derivatives bind to Histone Deacetylase 6 (HDAC6) at low binding energies, ranging from -6.54 to -9.84 kcal mol^-1, through metal complexation, hydrogen bonding, π-π stacking, and π-cation interactions, which correlates with their good antitumor activity. Compound 4-((2-fluoro-5,6-dihydro-7H-benzo[c]carbazol-7-yl)methyl)-N-hydroxybenzamide (13a) with the lowest binding energy of -9.84 kcal mol^-1 exhibited the best in vitro antitumor activity against MCF-7, with IC₅₀ of 1.98 μM.