Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling.

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFß-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

Recent contributions of pyridazine as a privileged scaffold of anticancer agents in medicinal chemistry: An updated review.

Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect.

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

Histone deacetylase 6 as a novel promising target to treat cardiovascular disease.

Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

Targeting cullin neddylation for cancer and fibrotic diseases.

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.

EZH2 serves as a promising therapeutic target for fibrosis.

Fibrosis affects the function of many organs and tissues, and its persistent development can lead to tissue sclerosis and cancer, even leading to death further. Recent studies suggested that enhancer of zeste homolog 2 (EZH2), a major regulator of epigenetic repression, played an important role in the occurrence and development of fibrosis through gene silencing or transcriptional activation. As the most studied and powerful pro-fibrotic cytokine closely related to EZH2, TGF-ß1 was primarily involved in the regulation of fibrosis along with the typical Smads and non-Smads signaling pathways. In addition, EZH2 inhibitors demonstrated inhibitory effects in several types of fibrosis. This review summarized the relationship underlying the action of EZH2, TGF-ß1/Smads, and TGF-ß1/non-Smads with fibrosis and described the research progress of EZH2 inhibitors in the treatment of fibrosis.

Lysine-Specific Demethylase 1 Promises to Be a Novel Target in Cancer Drug Resistance: Therapeutic Implications.

Chemotherapy, targeted therapy, and immunotherapy are effective against most tumors, but drug resistance remains a barrier to successful treatment. Lysine-specific demethylase 1 (LSD1), a member of histone demethylation modifications, can regulate invasion, metastasis, apoptosis, and immune escape of tumor cells, which are associated with tumorigenesis and tumor progression. Recent studies suggest that LSD1 ablation regulates resensitivity of tumor cells to anticarcinogens containing immune checkpoint inhibitors (ICIs) via multiple upstream and downstream pathways. In this review, we describe the recent findings about LSD1 biology and its role in the development and progression of cancer drug resistance. Further, we summarize LSD1 inhibitors that have a reversal or resensitive effect on drug resistance and discuss the possibility of targeting LSD1 in combination with other agents to surmount resistance.

The influence of polycystic ovary syndrome on abortion rate after in vitro fertilization/intracytoplasmic sperm injection fresh cycle pregnancy.

There are many reports on clinical pregnancy outcomes in polycystic ovary syndrome (PCOS) patients receiving vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), but little research about abortion has been done and there is a debate on whether the abortion risk increases in PCOS patients receiving IVF/ICSI. Therefore, the aim of this study was to investigated the abortion in PCOS patients. Clinical data of 12055 IVF/ICSI fresh cycles performed in our hospital from January 2015 to December 2020 were collected. Based on the Rotterdam diagnostic criteria of PCOS and after propensity score matching (PSM) for baseline data of clinical pregnancy cycles, matched 599 PCOS (PCOS group) and Non-PCOS (non-PCOS group) cycles were obtained. Abortion and abortion-related outcomes were compared between the two groups. Risk factors for late abortion in twins were analyzed using binary Logistics regression. Post-PSM data showed that the late abortion rate was significantly higher in the PCOS group than in the non-PCOS group only in twin pregnancy (9.50% vs. 3.96%, OR: 2.55, 95%CI 1.10-5.89). There were no statistical differences in other pregnancy outcomes. The etiological distribution for late abortion were not statistically different between the two groups in both singletons and twins. Logistics regression indicated that PCOS and obesity [pregnancy-assisted body mass index (BMI) ≥ 28] were risk factors for late abortion in twin pregnancy. In twin pregnancy, PCOS and obese patients are more likely to have late abortion. In twin pregnancy, the late abortion risk significantly increased in the PCOS patients as compared with non-PCOS patients (OR: 2.59, 95%CI 1.11-6.03, P < 0.05), as well as in the patients with obesity (BMI ≥ 28) as compared with the patients with normal BMI (OR: 4.17, 95%CI 1.59-10.90, P < 0.05). PCOS does not significantly affect early and overall late abortion rates after IVF/ICSI fresh cycle pregnancy.

Histone deacetylases (HDACs) as the promising immunotherapeutic targets for hematologic cancer treatment.

Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.

Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors.

Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma of the lung associated with early metastasis and an exceptionally poor prognosis. Little progress has been made in developing efficacious targeted therapy for this recalcitrant disease. Herein, we showed that H3.3, encoded by two genes (H3F3A and H3F3B), was prominently overexpressed in SCLC. Darinaparsin (ZIO-101), a derivative of arsenic trioxide, dose- and time-dependently inhibited the viability of SCLC cells in an H3.3-dependent manner. More importantly, ZIO-101 treatment resulted in substantial accumulation of H3.3 and PARP1 besides induction of G2/M cell cycle arrest and apoptosis in SCLC cells. Through integrative analysis of the RNA-seq data from Cancer Cell Line Encyclopedia dataset, JNCI and Genomics of Drug Sensitivity in Cancer 2 datasets, we found that H3F3A expression was negatively correlated with the IC50 values of PARP inhibitors (PARPi). Furthermore, co-targeting H3.3 and PARP1 by ZIO-101 and BMN673/olaparib achieved synergistic growth inhibition against SCLC in vitro and in vivo. In conclusion, it is feasible to target H3.3 by ZIO-101 to potentiate the response rate of PARPi in SCLC patients.

Design, synthesis and anti-tumor activity studies of novel pyrido[3, 4-d]pyrimidine derivatives.

In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4-d]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC50 = 0.59 µM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers.

Discovery of 1,3,4-oxadiazole derivatives containing a bisamide moiety as a novel class of potential cardioprotective agents.

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.

FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11.

The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

Enhancement of anticancer drug sensitivity in multidrug resistance cells overexpressing ATP-binding cassette (ABC) transporter ABCC10 by CP55, a synthetic derivative of 5-cyano-6-phenylpyrimidin.

ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10.

CMP25, a synthetic new agent, targets multidrug resistance-associated protein 7 (MRP7/ABCC10).

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity.

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors with promising anti-gastric cancer activities. Amongst, compound 9r displayed the best inhibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold selectivity over HDAC1. Further BLI and CETSA assay proved the high affinity of 9r to HDAC6. In addition, 9r could dose-dependently upregulate the levels of acetylated α-tubulin, without significant effect on acetylated histone H3 in MGC803 cells. Besides, 9r exhibited potent antiproliferative effect on MGC803 cells, and promoted apoptosis and suppressed the metastasis without obvious toxicity, suggesting 9r would serve as a potential lead compound for the development of novel therapeutic agents of gastric cancer.

Overcome the tumor immunotherapy resistance by combination of the HDAC6 inhibitors with antitumor immunomodulatory agents.

Tumor immunotherapy is currently subject of intense scientific and clinical developments. In previous decade, therapists used natural immune system from the human body to treat several diseases. Although tumor immune disease is a big challenge, combinatorial therapeutic strategy has been succeeded to show the clinical significance. In this context, we discuss the HDAC6 and tumor immune diseases relationship. Also, we summarized the current state of knowledge that based on the combination treatments of the HDAC6 inhibitors (HDAC6is) with antitumor immunomodulatory agents. We observed that, the combination therapies slow down the tumor immune diseases by blocking the aggresome and proteasome pathway. The combination therapy was able to reduce M2 macrophage and increasing PD-L1 blockade sensitivity. Most importantly, multiple combinations of HDAC6is with other agents may consider as potential strategies to treat tumor immune diseases, by reducing the side effects and improve efficacy for the future clinical development.

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity.

Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.

Current development of CBP/p300 inhibitors in the last decade.

CBP/p300, functioning as histone acetyltransferases and transcriptional co-factors, represents an attractive target for various diseases, including malignant tumor. The development of small-molecule inhibitors targeting the bromodomain and HAT domains of CBP/p300 has aroused broad interests of medicinal chemist in expectation of providing new hope for anti-cancer treatment. In particular, the CBP/p300 bromodomain inhibitor CCS1477, identified by CellCentric, is currently undergone clinical evaluation for the treatment of haematological malignancies and prostate cancer. In this review, we depict the development of CBP/p300 inhibitors reported from 2010 to 2020 and particularly highlight their structure-activity relationships (SARs), binding modes, selectivity and pharmacological functions with the aim to facilitate rational design and development of CBP/p300 inhibitors.