The ubiquitin‐proteasome system (UPS) is a complex process that regulates protein stability and activity by the sequential actions of E1, E2 and E3 enzymes to influence diverse aspects of eukaryotic ...cells. However, due to the diversity of proteins in cells, substrate selection is a highly critical part of the process. As a key player in UPS, E3 ubiquitin ligases recruit substrates for ubiquitination specifically. Among them, RING E3 ubiquitin ligases which are the most abundant E3 ubiquitin ligases contribute to diverse cellular processes. The multisubunit cullin‐RING ligases (CRLs) are the largest family of RING E3 ubiquitin ligases with tremendous plasticity in substrate specificity and regulate a vast array of cellular functions. The F‐box protein Skp2 is a component of CRL1 (the prototype of CRLs) which is expressed in many tissues and participates in multiple cellular functions such as cell proliferation, metabolism, and tumorigenesis by contributing to the ubiquitination and subsequent degradation of several specific tumor suppressors. Most importantly, Skp2 plays a pivotal role in a plethora of cancer‐associated signaling pathways. It enhances cell growth, accelerates cell cycle progression, promotes migration and invasion, and inhibits cell apoptosis among others. Hence, targeting Skp2 may represent a novel and attractive strategy for the treatment of different human cancers overexpressing this oncogene. In this review article, we summarized the known roles of Skp2 both in health and disease states in relation to the UPS.
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) ...transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.
The search for novel anticancer agents with more selectivity and lower toxicity continues to be an area of intensive investigation. The unique structural features of spirooxindoles together with ...diverse biological activities have made them privileged structures in new drug discovery. Among them, spiro-pyrrolidinyl oxindoles have been extensively studied as potent inhibitors of p53–MDM2 interaction, finally leading to the identification of MI-888, which could achieve rapid, complete and durable tumor regression in xenograft models of human cancer with oral administration and is in advanced preclinical research for cancer therapy. This review highlights recent progress of biologically active spirooxindoles for their anticancer potentials, mainly focusing on the discussions of SARs and modes of action. This article also aims to discuss potential further directions on the development of more potent analogues for cancer therapy.
This review describes recent progress of spirooxindoles as anticancer agents. SARs and modes of action are mainly discussed. Display omitted
•The spirooxindole is a promising scaffold for anticancer agents.•This review describes recent progress of spirooxindoles as anticancer agents.•SARs and modes of action are mainly discussed.
Biaryl scaffold is an important class of structural frameworks that exists in many natural products and drug molecules. The development of transition metal‐catalyzed approaches for the efficient ...construction of biaryl scaffolds has long been pursued because of the interesting structural features and broad biological profiles of biaryl scaffolds. Herein, we describe the Brønsted acid‐catalyzed direct C(sp2)−H heteroarylation that enables the synthesis of biaryl fragments (70 examples) in moderate to excellent yields (up to 99% yield), which was also performed at a gram scale and successfully applied to the privileged quinazoline scaffolds of the first‐generation epidermal growth factor receptor (EGFR) inhibitors Gefitinib and Erlotinib, offering rapid access to a series of quinazoline‐based biaryl compounds. Additionally, the late‐stage diversifications were performed based on the compound 3 b, generating a library of structurally diverse and complex biaryl compounds.
The combination of nanostructures with biomolecules leading to the generation of functional nanosystems holds great promise for biotechnological and biomedical applications. As a naturally occurring ...biomacromolecule, DNA exhibits excellent biocompatibility and programmability. Also, scalable synthesis can be readily realized through automated instruments. Such unique properties, together with Watson-Crick base-pairing interactions, make DNA a particularly promising candidate to be used as a building block material for a wide variety of nanostructures. In the past few decades, various DNA nanostructures have been developed, including one-, two- and three-dimensional nanomaterials. Aptamers are single-stranded DNA or RNA molecules selected by Systematic Evolution of Ligands by Exponential Enrichment (SELEX), with specific recognition abilities to their targets. Therefore, integrating aptamers into DNA nanostructures results in powerful tools for biosensing and bioimaging applications. Furthermore, owing to their high loading capability, aptamer-modified DNA nanostructures have also been altered to play the role of drug nanocarriers for
in vivo
applications and targeted cancer therapy. In this review, we summarize recent progress in the design of aptamers and related DNA molecule-integrated DNA nanostructures as well as their applications in biosensing, bioimaging and cancer therapy. To begin with, we first introduce the SELEX technology. Subsequently, the methodologies for the preparation of aptamer-integrated DNA nanostructures are presented. Then, we highlight their applications in biosensing and bioimaging for various targets, as well as targeted cancer therapy applications. Finally, we discuss several challenges and further opportunities in this emerging field.
We survey advances in biosensing, bioimaging and cancer therapy applications of aptamer-integrated DNA nanostructures in this review.
The quinazoline scaffold is prevalent in pharmaceutically relevant molecules that show diverse biological activities. Herein, we report an efficient “on‐water” palladium‐catalyzed tandem cyclization ...reaction from commercially available arylboronic acids and benzonitriles that enable the rapid access to 4‐arylquinazoline scaffolds in good to excellent yields (45 examples, up to 98 % yield). This protocol has shown good functional group tolerance and broad substrate scope. The reaction was also performed on a gram scale and successfully applied to the synthesis of the highly potent and selective PI3Kδ inhibitor N11, showing the practicability and synthetic utility of the protocol. In this reaction, the quinazoline scaffold is efficiently constructed with the simultaneous formation of one C−C bond and one C−N bond. Collectively, the protocol could serve as an alternative strategy to synthesize biologically important quinazoline scaffolds.
Better “on water”: An efficient palladium‐catalyzed tandem cyclization reaction from readily available arylboronic acids and benzonitriles on water has been developed to offer a rapid access to the quinazoline scaffolds in good to excellent yields (up to 98 % yield). This protocol is also performed on a gram scale and successfully applied to the synthesis of the highly potent and selective PI3Kδ inhibitor N11.
48 new drugs including 38 chemical entities (33 new chemical entities, 3 new diagnostic agents, and 2 payloads of antibody drug conjugates) and 10 biologics were approved by the U.S. Food and Drug ...Administration (FDA) during 2019. These marketed new drugs represent privileged structures and novel action of mechanism, and thus can be served as leads to discover new drugs with the similar biological targets and improved therapeutic efficacy. This review aims to provide an overview regarding the synthetic approaches of 33 new chemical entities approved by the FDA in 2019 and their clinical applications.
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•48 new drugs were approved by the FDA during 2019.•These new drugs represent privileged structures and could also serve as leads to discover new drugs.•The synthetic approaches of 33 new chemical entities and their clinical applications are summarized.
Histone lysine‐specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the ...common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono‐ or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde‐generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor‐cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer‐cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.
Objective This prospective multicenter comparative study examined early and midterm results of medication and stent-graft therapies on chronic type B aortic dissection in China. Methods The study ...consisted of 303 consecutive patients with chronic type B aortic dissection from four centers in China from January 2007 to December 2010 who were prospectively enrolled and treated by either optimal medical therapy (OMT) or thoracic endovascular aorta repair (TEVAR). Of the patients, 219 were male and 84 were female (average age, 53.6 ± 20.3 years; range, 29-81 years). Baseline diameter of the thoracic aorta was 41.2 (19.1) mm (mean standard deviation), and dissection extended beyond the celiac axis in 87.1% of cases. Results In total, there were 208 patients in the TEVAR group and 95 patients in the OMT group. Procedural success was 100%, and no deaths occurred during index hospitalization in the two groups. In the TEVAR group, two patients (0.9%) suffered from retrograde type A dissection, and two (0.9%) suffered from paraplegia or paraparesis. For in-hospital outcome, multivariate analysis revealed that age >75 years and American Society of Anesthesiologists class greater than III were independent predictors of major early adverse events. Average follow-up time for hospital survivors was 28.5 ± 16.3 months (range, 1.0-58 months). In the OMT group, five patients died from rupture of an enlarged false lumen, and six patients died suddenly of unknown reasons. Fourteen cases required crossover to TEVAR (n = 12) or surgical conversion (n = 2). In the TEVAR group, nine patients required reintervention or surgical conversion, and one died of postoperative multi-organ failure. One patient died of delayed retrograde type A dissection, and four died suddenly of unknown reasons. The Kaplan-Meier analysis of survival probability at 2 and 4 years was 87.5% and 82.7% with TEVAR, respectively, and 77.5% and 69.1% with OMT, respectively ( P = .0678, log-rank test). The estimated cumulative freedom from aorta-related death at 2 and 4 years was 91.6% and 88.1% with TEVAR, respectively, and 82.8% and 73.8% with OMT, respectively ( P = .0392, log-rank test). The thoracic aorta diameter decreased from 42.4 (23.1) mm to 37.3 (12.8) mm in the TEVAR group and increased from 40.7 (18.6) mm to 48.1 (17.3) mm in the OMT group. Conclusions This was the first prospective multicenter comparative study on the treatment of type B aortic dissection in China. TEVAR had a significantly lower aorta-related mortality compared with OMT but failed to improve overall survival rate or lower the aorta-related adverse event rate.
Lysine‐specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono‐, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the ...suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1‐targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.
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