Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies.

Histone methyltransferases (HMTs) play a critical role in gene post-translational regulation and diverse physiological processes, and are implicated in a plethora of human diseases, especially cancer. Increasing evidences demonstrate that HMTs may serve as a potential therapeutic target for cancer treatment. Thus, the development of HMTs inhibitor have been pursued with steadily increasing interest over the past decade. However, the disadvantages such as insufficient clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of conventional HMT inhibitors. New technologies and methods are imperative to enhance the anticancer activity of HMT inhibitors. In this review, we first review the structure and biological functions of the several essential HMTs, such as EZH2, G9a, PRMT5, and DOT1L. The internal relationship between these HMTs and cancer is also expounded. Next, we mainly focus on the latest progress in the development of HMT modulators encompassing dual-target inhibitors, targeted protein degraders and covalent inhibitors from perspectives such as rational design, pharmacodynamics, pharmacokinetics, and clinical status. Lastly, we also discuss the challenges and future directions for HMT-based drug discovery for cancer therapy.

Exploring the potential of histone demethylase inhibition in multi-therapeutic approaches for cancer treatment.

Histone demethylases play a critical role in gene transcription regulation and have been implicated in cancer. Numerous reports have highlighted the overexpression of histone demethylases, such as LSD1 and JmjC, in various malignant tumor tissues, identifying them as effective therapeutic targets for cancer treatment. Despite many histone demethylase inhibitors entering clinical trials, their clinical efficacy has been limited. Therefore, combination therapies based on histone demethylase inhibitors, along with other modulators like dual-acting inhibitors, have gained significant attention and made notable progress in recent years. In this review, we provide an overview of recent advances in drug discovery targeting histone demethylases, focusing specifically on drug combination therapy and histone demethylases-targeting dual inhibitors. We discuss the rational design, pharmacodynamics, pharmacokinetics, and clinical status of these approaches. Additionally, we summarize the co-crystal structures of LSD1 inhibitors and their target proteins as well as describe the corresponding binding interactions. Finally, we also provided the challenges and future directions for utilizing histone demethylases in cancer therapy, such as PROTACs and molecular glue etc.

Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma.

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 µM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 µM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

Discovery of Novel Acridane-Based Tubulin Polymerization Inhibitors with Anticancer and Potential Immunomodulatory Effects.

A series of novel acridane-based tubulin polymerization inhibitors were designed, synthesized, and bioevaluated as anticancer agents. The most potent compound NT-6 exhibited high tubulin polymerization inhibitory activity (IC50 = 1.5 µM) and remarkable antiproliferative potency against four cancer cell lines with an average IC50 of 30 nM, better than colchicine and the hit compound 1f (IC50 of 65 and 126 nM, respectively). In addition, NT-6 (10 mg/kg) exerted excellent antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 65.1% without apparent toxicity. Importantly, the combination of NT-6 with a small-molecule PD-L1 inhibitor NP-19 decreased tumor burden significantly (TGI% = 77.6%). Moreover, the combination of NT-6 with NP-19 enhanced the antitumor immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of antitumor CD8+ effector T cells in tumor tissues. Collectively, NT-6 represents a novel tubulin polymerization inhibitor with immunopotentiating effects.

Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy.

Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.

The Chemical Compositions of Angelica pubescens Oil and Its Prevention of UV-B Radiation-Induced Cutaneous Photoaging.

Angelica pubescens, a plant of the family Umbelliferae, has been widely used as traditional Chinese medicine for the treatment of many diseases. However, there has been minimal modern research focused on the pharmacological activity of oils extracted from Angelica pubescens, in particular, the potential anti-photoaging effects. Therefore, in the present study, we analyzed the chemical composition of Angelica pubescens oil (AO) and evaluated its bioactivity against photoaging in ultraviolet (UV) -B radiation-induced hairless mice. Overall, we identified and analyzed 93 compounds from the AO by gas chromatography-mass spectrometry (GC/MS). The top ten compounds were as follows: osthole (44.608%), glutaric acid hexadecyl pent-4-en-1-yl ester (5.758%), α-bisabolol (3.795%), eugenol (3.637%), (Z)-docos-13-enamide (3.286%), (3S,3aR)-3-butyl-3a,4,5,6-tetrahydro-3H-2-benzofuran-1-one (3.043%), m-cresol (2.841%), trans-sesquisabinene hydrate (2.128%), 4-hydroxy-2-methylacetophenone (1.735%), and (Z)-9-pentadecenol (1.509%). Application of AO improved the condition of UV-B radiation-induced damaged skin, and the mechanism of action was found to be related to inhibition of the production of inflammatory cytokines. These results highlight the potential application of AO for the development of skin care products.

Distribution and diversity of twelve Curcuma species in China.

Genus Curcuma a wild species presents an important source of valuable characters for improving the cultivated Curcuma varieties. Based on the collected germplasms, herbariums, field surveys and other literatures, the ecogeographical diversity of Genus Curcuma and its potential distributions under the present and future climate are analysed by DIVA-GIS. The results indicate Genus Curcuma is distributed over 17 provinces in China, and particularly abundant in Guangxi and Guangdong provinces. The simulated current distributions are close to the actual distribution regions. In the future climate, the suitable areas for four Curcuma species will be extended, while for other three species the regions will be significantly decreased, and thus these valuable resources need protecting.

Variation on Composition and Bioactivity of Essential Oils of Four Common Curcuma Herbs.

Chemical compositions, antioxidative, antimicrobial, anti-inflammatory, and cytotoxic activities of essential oils extracted from four common Curcuma species (Curcuma longa, Curcuma phaeocaulis, Curcuma wenyujin, and Curcuma kwangsiensis) rhizomes in P. R. China are comparatively studied. In total, 47, 49, 35, and 30 compounds are identified in C. longa, C. phaeocaulis, C. wenyujin, and C. kwangsiensis essential oils by GC/MS, and their richest compounds are ar-turmerone (21.67%), elemenone (19.41%), curdione (40.23%) and (36.47%), respectively. Moreover, C. kwangsiensis essential oils display the strongest DPPH (2,2-diphenyl-1-picrylhydrazyl) radical-scavenging activity (IC50 , 3.47 µg/ml), much higher than ascorbic acid (6.50 µg/ml). C. phaeocaulis oils show the best antibacterial activities against Escherichia coli (MIC, 235.54 µg/ml), Pseudomonas aeruginosa (391.31 µg/ml) and Staphylococcus aureus (378.36 µg/ml), while C. wenyujin and C. kwangsiensis oils show optimum activities against Candida albicans (208.61 µg/ml) and Saccharomyces cerevisiae (193.27 µg/ml), respectively. C. phaeocaulis (IC50 , 4.63 µg/ml) and C. longa essential oils (73.05 µg/ml) have the best cytotoxicity against LNCaP and HepG2, respectively. C. kwangsiensis oils also exhibit the strongest anti-inflammatory activities by remarkably down-regulating expression of COX-2 and TNF-α. Therefore, due to their different chemical compositions and bioactivities, traditional Chinese Curcuma herbs should be differentially served as natural additives for food, pharmaceutical, and cosmetic.

[Comparison and bias estimation of three methods in determination of glycated hemoglobin A1c].

OBJECTIVE: To evaluate the bias of three different methods in determination of glycated hemoglobin A1c (HbA1c). METHODS: According to Clinical and Laboratory Standards Institute (CLSI)EP9-A3 document, 40 serum specimens among linear range were tested by immunoturbidimetry assay (Roche Tina-quant), capillary electrophoresis (Sebia Minicap FP), high performance liquid chromatography system (HPLC, Trinity Biotech Premier Hb 9210™). RESULTS were analyzed by pairwise comparision. The difference plots and scatter plots were analyzed. The results of outliers were examined by extreme studentized deviate (ESD) method. The best regression model was chosen to fit the regression equation and the biases were calculated at the level of medical decision and judged the comparability according to the half of Tea acceptance standard. RESULTS: Scatter plots and ESD results showed good correlation among test results of 40 samples, no abnormal values were found. Based on proportional difference deviation plots, proportional difference rank order deviation plots, numerical deviation plots and ranked order difference plots, weighted least squares (WLS) (Roche(X) vs sebia(Y1)), ordinary linear regression (OLR) (Roche(X) vs Trinity (Y2)) and Deming (Sebia(Y1) vs Trinity(Y2)) were chosen to fit regression analysis model. The regression equations were Y1 =-0.420 3+ 1.052 7X, Y2 =-0.174 0+ 1.027 0X, Y2=0.423 1+ 0.959 0Y1, respectively. Assuming the HbA1c medical decision points of 10%, 16% to regression equation, the proportional biases were 1.06% and 2.61% at Roche(X) and sebia(Y1) system, 0.96% and 1.60% at Roche(X) and Trinity (Y2) system, 0.13% and -1.47% at Sebia(Y1) and Trinity(Y2) system respectively, which were all lower than the acceptable values. CONCLUSION: The measurement values of HbA1c by capillary electrophoresis (Sebia Minicap FP), HPLC (Trinity Biotech Premier Hb 9210™) and immunoturbidimetry assay (Roche Tina-quant), are comparable.