Drug discovery of sclerostin inhibitors

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.

Application of Nuclear Imaging Probes in PD-L1 Immunotherapy of Tumor / 肿瘤防治研究

Immunotherapy strategies of targeting PD-1 and its ligand PD-L1 are widely administered in varied types of cancer. Patient benefitting from PD-L1 targeted immunotherapy mainly depends on the expression level of PD-L1 in tumor tissues. Currently, the expression level of PD-L1 is primarily detected through the invasive method of biopsy in clinic, which is severely limited by the temporal and spatial heterogeneity of PD-L1 expression. Nuclear medicine probe can realize the noninvasive as well as in vivo detection of PD-L1 at the molecular level, which has important clinical significance for the guidance of patient screening and the prediction of patient's response to immunotherapy. This article reviews PD-L1 targeting nuclear imaging probes and their applications in tumor PD-L1 imaging.

Advances in Treatment of Transfusion-dependent Lower-risk Myelodysplastic Syndromes / 肿瘤防治研究

At present, the patients with transfusion-dependent lower-risk myelodysplastic syndromes (MDS) have limited treatment options when erythropoiesis-stimulating agent is ineffective or relapsed. With more understanding of the pathological and molecular genetics characteristics of MDS, the development of precise medical treatment of MDS has been promoted. Small-molecule inhibitors, such as transforming growth factor β inhibiter, telomerase inhibiter and hypoxia-inducible factor prolyl hydroxylase inhibitor, provide novel therapeutic strategies for patients. This article reviews the treatment of transfusion-dependent lower-risk MDS patients and discusses the latest clinical research and development of novel targeted agents.

Diverse Effects of Small Molecule Inhibitors on Actin Cytoskeleton Dynamics in HIV-1 Infection

The dynamics of the actin cytoskeleton plays a pivotal role in the process of cell division, the transportation of organelles, vesicle trafficking and cell movement. Human immunodeficiency virus type 1 (HIV-1) hijacks the actin dynamics network during the viral entry and migration of the pre-integration complex (PIC) into the nucleus. Actin dynamics linked to HIV-1 has emerged as a potent therapeutic target against HIV infection. Although some inhibitors have been intensely analyzed with regard to HIV-1 infection, their effects are sometimes disputed and the exact mechanisms for actin dynamics in HIV infection have not been well elucidated. In this study, the small molecules regulating HIV-1 infection from diverse inhibitors of the actin dynamic network were screened. Two compounds, including Chaetoglobosin A and CK-548, were observed to specifically bar the viral infection, while the cytochalasin family, 187-1, N-WASP inhibitor, Rho GTPase family inhibitors (EHop-016, CID44216842, and ML-141) and LIMK inhibitor (LIM domain kinase inhibitor) increased the viral infection without cytotoxicity within a range of ~ µM. However, previously known inhibitory compounds of HIV-1 infection, such as Latrunculin A, Jasplakinolide, Wiskostatin and Swinholide A, exhibited either an inhibitory effect on HIV-1 infection combined with severe cytotoxicity or showed no effects. Our data indicate that Chaetoglobosin A and CK-548 have considerable potential for development as new therapeutic drugs for the treatment of HIV infection. In addition, the newly identified roles of Cytochalasins and some inhibitors of Rho GTPase and LIMK may provide fundamental knowledge for understanding the complicated actin dynamic pathway when infected by HIV-1. Remarkably, the newly defined action modes of the inhibitors may be helpful in developing potent anti-HIV drugs that target the actin network, which are required for HIV infection.

Research advances in small molecule inhibitors of botulinum neurotoxins / 中国药理学与毒理学杂志

Botulinum neurotoxins (BoNTs) are the most deadly biological substances, including seven BoNT serotypes (A-G), and characterized by persistent flaccid paralysis of peripheral never terminals with high specificity called botulism. Due to their easy production and well-defined biological mechanism, BoNTs are wildly used in cosmetics and as very particular biopharmaceuticals in clinical therapy, so there is the risk of poisoning caused by accidental overdose. Also, because of their high toxicity, they are potential bioterrorism weapons. Thus, there is an urgent need for the development of BoNT inhibitors. In this review, based on the structure of BoNTs and the mechanism of botulism, we summarize recent advances in small molecule inhibitors targeting the Zn2+ active site of BoNT/A, such as 8-hydroxyquinoline and hydroxamic acid, or exosite of BoNT/A, small molecule inhibitors of BoNT/A through covalent binding that are irreversible, as well as small molecule inhibitors of targeting BoNT/B/ E light chain (LC).

Progress in targeted therapy of tumor KRAS gene mutation / 中国药理学通报

Targeting KRAS mutations has always been a difficult issue in clinical tumor therapy as most tumors are accompanied by KRAS gene mutations, which indicate poor prognosis. The mutant KRAS protein is difficult to design specific inhibitors in the conventional way of inhibiting the active sites, which is known as "undmggble" target. Therefore, the exploration of drug strategies targeting KRAS mutations has become a hot spot in the research and development of antitumor drugs. Although the research progress of targeted KRAS treatment strategy is limited, some new strategies that directly or indirectly inhibit mutant KRAS are still emerging in view of the deepening understanding of KRAS mutation function and malignant mechanism. In this review, we discussed the research progress of targeted therapy for KRAS gene mutation in tumor, hoping to provide the latest clues for the treatment of KRAS mutant tumor.

The construction of pharmacophore model for(1,3)-β-D-glucan synthase small molecule inhibitors / 药学实践杂志

Objective To perform the ligand-based computer-aided drug design and construct the pharmacophore model of(1,3)-β-D-Glucan Synthase(GS)small molecule inhibitors.Method Six small molecules with diverse structures and good inhibitory activity were selected to construct the training set.The HipHop algorithm in Catalyst pharmacophore generation module was utilized to construct the pharmacophore models.The pharmacophore models were evaluated by constructed Decoy-set 3D database.Results Pharmacophore 02 has a good enrichment factor,sensitivity and specificity parameters.Pharmacoph-ore model validation with Decoyset 3D database proved that the model has good distinguishing capability.Conclusion The pharmacophore model of GS small molecule inhibitors was constructed and tested.It will provide valuable information for de-sign and discovery of novel small molecule GS inhibitors.

BET Bromodomain inhibitors and degraders based on polypharmacology:research advances / 国际药学研究杂志

Bromodomain and extra-terminal domain(BET)Bromodomain has become a new target for the treatment of cancers and other human disorders. Nowadays,several classes of its potent and selective small-molecule inhibitors have been identified,many of which are in clinical trials. Preclinical and clinical data have shown that BET Bromodomain inhibitors have good prospects. Howev-er,there are potential therapeutic deficiencies,such as drug resistance. At present,attempts are being made to develop BET Bromodo-main inhibitors and degraders based on polypharmacology,combining BET Bromodomain with other targets of different mechanisms. In this paper,small-molecule kinase/BET inhibitors,small-molecule histone deacetylases(HDAC)/BET inhibitors and BET protein degraders are reviewed,which may provide guidance for further research on BET protein.

Developing high quality chemical probes targeting ubiquitin-specific proteases / 中国药理学与毒理学杂志

Ubiquitin-specific proteases (USPs) regulate the deconjugation of ubiquitin tag from substrate proteins. Dysregulation of USPs has been linked to many diseases. Despite extensive efforts by academia and industry,high quality chemical molecules targeting the USPs family of ubiquitin enzymes are still scarce. In this commentary,I propose the criteria of a high quality chemical probe and the strategies to target USPs.

Topical drugs for the treatment of psoriasis / 中华皮肤科杂志

In recent years, great progress has been made in the pathogenesis of psoriasis, which has provided multiple new targets for the treatment of psoriasis, and ushered the treatment, especially topical treatment, of psoriasis to a new era. Some new targeted topical drugs with action mechanisms different from those of traditional drugs have been applied in clinical practice, which are mainly small -molecule inhibitors targeting cell signaling pathways or enzymes involved in the pathogenesis of psoriasis, such as the Janus kinase/signal transducer and activator of transcription(JAK/STAT) pathway, phosphodiesterase type 4 (PDE4), mitogen-activated/extracellular-signal-regulated kinase kinase (MEK), vascular endothelial growth factor receptor (VEGFR), tropomyosin receptor kinase A (TrKA), retinoic acid receptor-related orphan receptor γ (RORγ), and so on. At present, many phaseⅠ and Ⅱ clinical trials are conducted for these drugs. Some completed trials have shown that they have good effectiveness, safety and tolerance, providing more options for the topical treatment of psoriasis.

Targeting B-cell receptor signaling: Changing the treatment landscape of B-cell Lymphoma.

Introduced in 1998, the anti-CD20 monoclonal antibody rituximab, with its unique mechanism of action, was the first agent to improve survival in patients with B-cell lymphoma (BCL) treated with chemotherapy. Laboratory investigation of the B-cell receptor signaling pathway identified the critical nature of this pathway for normal B-cell development, survival and proliferation. Further investigation showed that lymphoma cell lines were also dependent upon this pathway and hence small molecule inhibitors of critical proteins in the pathway were synthesized and shown to be cytotoxic. Subsequent translation to the clinic has shown impressive activity in some types of B-cell lymphoma. The aim of this article is to provide an overview of the constituents of the BCR signaling pathway, to illustrate how addiction to this pathway is critical for survival of some BCL, and to summarize the clinical experience with novel small molecule inhibitors of specific proteins in the BCR pathway. We speculate that combination of these agents with newer drugs, each with a unique mechanism of action might lead to improved therapy and the eventual elimination of standard chemotherapy from our therapeutic arsenal.

Small-molecule aggregation inhibitors reduce excess amyloid in a trisomy 16 mouse cortical cell line

We have previously characterized a number of small molecule organic compounds that prevent the aggregation of the β-amyloid peptide and its neurotoxicity in hippocampal neuronal cultures. We have now evaluated the effects of such compounds on amyloid precursor protein (APP) accumulation in the CTb immortalized cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down's syndrome. Compared to a non-trisomic cortical cell line (CNh), CTb cells overexpress APP and exhibit slightly elevated resting intracellular Ca2+ levéis ([Ca2+]¡). Here, we show that the compounds 2,4-dinitrophenol, 3-nitrophenol and 4-anisidine decreased intracellular accumulation of APP in CTb cells. Those compounds were non-toxic to the cells, and slightly increased the basal [Ca2+]¡. Results indícate that the compounds tested can be leads for the development of drugs to decrease intracellular vesicular accumulation of APP in trisomic cells.

Design and discovery of novel small-molecule inhibitor of CDK9 / 中国药理学通报

Aim To look for novel small-molecule inhibitors of CDK9 through structure-based virtual screening and biological activity determination.Methods Homology modeling of CDK9 was based on the 3-D structure of other cyclin-dependent kinase family members,and then virtual screening by DOCK(molecular docking)of database of small molecule was carried on.MTT method was used in inhibition of tumor cell growth in vitro,while Western blot was used for further study of molecular mechanisms.Results From the top 1000 compounds with the best DOCK energy score,27 compounds were selected for biological assay based on the diversity of chemical structure and functional group.12 of 27 selected compounds showed significantly inhibition activity on tumor cell proliferation,and only one compound in 12 with half-maximum inhibition concentration(IC50)values less than 20 ?mol?L-1 named C-21 was selected for further molecular mechanism study.The western blotting data showed C-21 compound could effectively inhibit CDK9 from phosphorylating large subunit C-terminal of RNA polymerase Ⅱ in a dose-dependent manner.Conclusions Through homology modeling,virtual screening by computer,determination of biological activity and experimental studies of molecular mechanism,a new promising lead compound targeted for CDK9 was found and confirmed.