Synthetic approaches and clinical application of representative small-molecule inhibitors of phosphodiesterase.

Phosphodiesterases (PDEs) constitute a family of enzymes that play a pivotal role in the regulation of intracellular levels of cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Dysregulation of PDE activity has been implicated in diverse pathological conditions encompassing cardiovascular disorders, pulmonary diseases, and neurological disorders. Small-molecule inhibitors targeting PDEs have emerged as promising therapeutic agents for the treatment of these ailments, some of which have been approved for their clinical use. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation PDE inhibitors. The objective of this review is to provide an overview of the synthesis and clinical application of representative approved small-molecule PDE inhibitors, with the aim of offering guidance for further advancements in the development of novel PDE inhibitors.

Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy.

This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.

Synthetic approaches and application of representative clinically approved fluorine-enriched anti-cancer medications.

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.

Synthetic Approaches and Clinical Application of Representative Small-Molecule Inhibitors of Cyclin-Dependent Kinase for Cancer Therapy.

The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy.

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice.

BACKGROUND: The inflammation and synaptic dysfunction induced by mitochondrial dysfunction play essential roles in the learning and memory impairment associated with sleep dysfunction. Elamipretide (SS-31), a novel mitochondrion-targeted antioxidant, was proven to improve mitochondrial dysfunction, the inflammatory response, synaptic dysfunction, and cognitive impairment in models of cerebral ischemia, sepsis, and type 2 diabetes. However, the potential for SS-31 to improve the cognitive impairment induced by chronic sleep deprivation (CSD) and its underlying mechanisms is unknown. METHODS: Adult c57BL/6J mice were subjected to CSD for 21 days using an activity wheel accompanied by daily intraperitoneal injection of SS-31 (5 mg/kg). The novel object recognition and Morris water maze test were used to evaluate hippocampus-dependent cognitive function. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine the effects of CSD and SS-31 on markers of mitochondria, inflammation response, and synaptic function. Enzyme-linked immunosorbent assays were used to examine the levels of proinflammatory cytokines. RESULTS: SS-31 could improve the cognitive impairment induced by CSD. In particular, SS-31 treatment restored the CSD-induced decrease in sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator alpha levels and the increase in levels nuclear factor kappa-B and inflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha. Furthermore, SS-31 significantly increased the levels of brain-derived neurotrophic factor, postsynaptic density protein-95, and synaptophysin in CSD mice. CONCLUSION: Taken together, these results suggest that SS-31 could improve CSD-induced mitochondrial biogenesis dysfunction, inflammatory response, synaptic dysfunction, and cognitive impairment by increasing SIRT1 expression levels.

Crosstalk of cuproptosis-related subtypes, establishment of a prognostic signature, and immune infiltration characteristics in gastric cancer.

Background: Cuproptosis is a novel form of cellular demise that occurs through a unique pathway involving lipoylated proteins in the tricarboxylic acid (TCA) cycle and is closely linked to mitochondrial metabolism. Nevertheless, the comprehensive elucidation of the impact of carcinogenesis-associated genes (CRGs) on prognosis, tumor microenvironment (TME), and therapeutic response in patients with gastric cancer (GC) remains unclear. Methods: In total, 1374 GC samples were gathered from three Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas database. The samples were then stratified into different subtypes through unsupervised clustering of the 13 CRG profiles. The CRG_score was developed to quantify CRG patterns of individual tumors. Subsequently, we investigated the associations among the various groups and clinicopathological features, immune infiltration features, TME mutation status, and response to immunotherapy. Results: The GC samples were divided into two clusters based on their distinct clinicopathological features, prognosis, and immune characteristics. Using LASSO and Cox regression analyses, 9 genes were identified for constructing a prognostic signature related to cuproptosis. The novel signature displayed outstanding durability and prognostic capability for the overall lifespan of individuals. Additionally, the expression levels of signature genes in GC tissues and adjacent normal tissues were tested by qRT-PCR. Moreover, we developed a remarkably dependable nomogram to enhance the practicality of the CRG_score in clinical settings. High tumor mutation burden, increased microsatellite instability-high, immune activation, along with good survival probability and increased immunoreactivity to immune checkpoint inhibitors, were distinguishing features of low CRG_scores. Conclusions: The findings of this study revealed the possible impacts of CRGs on the TME, clinical and pathological characteristics, and outlook of patients with GC. This signature was strongly linked to the immune response against GC and has the potential to serve as a valuable tool for predicting patient prognosis.

DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis.

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

Synthesis and clinical application of new drugs approved by FDA in 2023.

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies.

Harmonizing the craft of crafting clinically endorsed small-molecule BCR-ABL tyrosine kinase inhibitors for the treatment of hematological malignancies.

The advancement and practical use of small-molecule tyrosine kinase inhibitors (TKIs) that specifically target the BCR-ABL fusion protein have introduced a revolutionary era of precision medicine for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This review offers a comprehensive exploration of the synthesis, mechanisms of action, and clinical implementation of clinically validated TKIs in the context of BCR-ABL, emphasizing the remarkable strides made in achieving therapeutic precision. We delve into the intricate design and synthesis of these small molecules, highlighting the synthetic strategies and modifications that have led to increased selectivity, enhanced binding affinities, and reduced off-target effects. Additionally, we discuss the structural biology of BCR-ABL inhibition and how it informs drug design. The success of these compounds in inhibiting aberrant kinase activity is a testament to the meticulous refinement of the synthetic process. Furthermore, this review provides a detailed analysis of the clinical applications of these TKIs, covering not only their efficacy in achieving deep molecular responses but also their impact on patient outcomes, safety profiles, and resistance mechanisms. We explore ongoing research efforts to overcome resistance and enhance the therapeutic potential of these agents. In conclusion, the synthesis and utilization of clinically validated small-molecule TKIs targeting BCR-ABL exemplify the transformative power of precision medicine in the treatment of hematological malignancies. This review highlights the evolving landscape of BCR-ABL inhibition and underscores the continuous commitment to refining and expanding the therapeutic repertoire for these devastating diseases.

A Comprehensive Review of Small-Molecule Inhibitors Targeting Bruton Tyrosine Kinase: Synthetic Approaches and Clinical Applications.

Bruton tyrosine kinase (BTK) is an essential enzyme in the signaling pathway of the B-cell receptor (BCR) and is vital for the growth and activation of B-cells. Dysfunction of BTK has been linked to different types of B-cell cancers, autoimmune conditions, and inflammatory ailments. Therefore, focusing on BTK has become a hopeful approach in the field of therapeutics. Small-molecule inhibitors of BTK have been developed to selectively inhibit its activity and disrupt B-cell signaling pathways. These inhibitors bind to the active site of BTK and prevent its phosphorylation, leading to the inhibition of downstream signaling cascades. Regulatory authorities have granted approval to treat B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with multiple small-molecule BTK inhibitors. This review offers a comprehensive analysis of the synthesis and clinical application of conventional small-molecule BTK inhibitors at various clinical stages, as well as presents promising prospects for the advancement of new small-molecule BTK inhibitors.

Synthesis and clinical application of small-molecule drugs approved to treat prostatic cancer.

Prostate cancer is a prevalent form of cancer that primarily affects men, with a high incidence and mortality rate. It is the second most common cancer among males, following lung cancer. Typically occurring in individuals aged 50 and above, this malignant tumor originates from abnormal cells in the prostate tissue. If left untreated, it can spread to nearby tissues, lymph nodes, and even bones. Current treatment methods include surgery, radiotherapy, and chemotherapy. However, these treatments have certain limitations and side effects. Therefore, researching and developing new small-molecule drugs to treat prostate cancer is of great significance. In recent years, many small-molecule drugs have been proven to have therapeutic effects on prostate cancer. The purpose of this review is to give a comprehensive look at the clinical uses and synthetic methods of various significant small-molecule drugs that have been approved to treat prostate cancer, to facilitate the development of more powerful and innovative drugs for the effective control of prostate cancer.

Synthetic approaches and application of clinically approved small-molecule drugs to treat hepatitis.

Hepatitis, a global public health concern, presents a significant burden on healthcare systems worldwide. Particularly, hepatitis B and C are viral infections that can lead to severe liver damage, cirrhosis, and even hepatocellular carcinoma (HCC). The urgency to combat these diseases has driven researchers to explore existing small-molecule drugs as potential therapeutics. This comprehensive review provides a systematic overview of synthetic routes to key antiviral agents used to manage hepatitis. Furthermore, it elucidates the mechanisms of action of these drugs, shedding light on their interference with viral replication and liver disease progression. The review also discusses the clinical applications of these drugs, including their use in combination therapies and various patient populations. By evaluating the synthetic pathways and clinical utility of these drugs, this review not only consolidates current knowledge but also highlights potential future directions for research and drug development in the fight against hepatitis, ultimately contributing to improved patient outcomes and reduced global disease burden.

Synthesis and clinical application of small-molecule inhibitors of Janus kinase.

Janus kinase (JAK) plays a crucial role in intracellular signaling pathways, particularly in cytokine-mediated signal transduction, making them attractive therapeutic targets for a wide range of diseases, including autoimmune disorders, myeloproliferative neoplasms, and inflammatory conditions. The review provides a comprehensive overview of the development and therapeutic potential of small-molecule inhibitors targeting JAK family of proteins in various clinical trials. It also discusses the mechanisms of action, specificity, and selectivity of these inhibitors, shedding light on the challenges associated with achieving target selectivity while minimizing off-target effects. Moreover, the review offers insights into the clinical applications of JAK inhibitors, summarizing the ongoing clinical trials and the Food and Drug Administration (FDA)-approved JAK inhibitors currently available for various diseases. Overall, this review provides a thorough examination of the synthesis and clinical use of typical small-molecule JAK inhibitors in different clinical stages and offers a bright future for the development of novel small-molecule JAK inhibitors.

Advances of clinically approved small-molecule drugs for the treatment of non-small cell lung cancer.

Lung cancer continues to pose a significant challenge as a prominent contributor to global cancer-related mortality. Despite the considerable strides made in therapeutic interventions within the past decade, a substantial population of patients diagnosed with non-small cell lung cancer (NSCLC) still face the grim reality of an incurable condition. In the realm of optimal management strategies for individuals afflicted with locally advanced, yet amenable to surgical resection, NSCLC, a therapeutic approach encompassing chemoradiation stands as a fundamental component. Significant strides have been made in the therapeutic landscape of NSCLC during the preceding two decades, facilitating an enhanced comprehension of the underlying disease biology, and mechanisms governing tumor progression, as well as advancements in early detection modalities and multimodal therapeutic interventions. Nevertheless, the overall rates of curative interventions and survival outcomes for NSCLC continue to exhibit a discouragingly low trajectory, particularly in the context of metastatic disease. Hence, the imperative for sustained research endeavors in the realm of novel pharmaceutical agents and combinatorial therapeutic approaches remains paramount, with the overarching objective of broadening the scope of clinical advantages conferred upon a wider demographic of patients, thereby fostering tangible improvements in outcomes pertaining to NSCLC. The primary objective of this review is to provide an all-encompassing examination encompassing the clinical application and synthetic routes of specific drugs, with the explicit aim of disseminating invaluable knowledge that can inform future research and development endeavors focused on NSCLC.

Synthesis and clinical application of new drugs approved by FDA in 2022.

The pharmaceutical industry had a glorious year in 2022, with a total of 37 new drugs including 20 new chemical entities (NCEs) and 17 new biological entities (NBEs) approved by the Food and Drug Administration (FDA). These drugs are mainly concentrated in oncology, central nervous system, antiinfection, hematology, cardiomyopathy, dermatology, digestive system, ophthalmology, MRI enhancer and other therapeutic fields. Of the 37 drugs, 25 (68%) were approved through an expedited review pathway, and 19 (51%) were approved to treat rare diseases. These newly listed drugs have unique structures and new mechanisms of action, which can serve as lead compounds for designing new drugs with similar biological targets and enhancing therapeutic efficacy. This review aims to outline the clinical applications and synthetic methods of 19 NCEs newly approved by the FDA in 2022, but excludes contrast agent (Xenon Xe-129). We believe that an in-depth understanding of the synthetic methods of drug molecules will provide innovative and practical inspiration for the development of new, more effective, and practical synthetic techniques. According to the therapeutic areas of these 2022 FDA-approved drugs, we have classified these 19 NCEs into seven categories and will introduce them in the order of their approval for marketing.

Recent advance of clinically approved small-molecule drugs for the treatment of myeloid leukemia.

Myeloid leukemia denotes a hematologic malignancy characterized by aberrant proliferation and impaired differentiation of blood progenitor cells within the bone marrow. Despite the availability of several treatment options, the clinical outlook for individuals afflicted with myeloid leukemia continues to be unfavorable, making it a challenging disease to manage. Over the past, substantial endeavors have been dedicated to the identification of novel targets and the advancement of enhanced therapeutic modalities to ameliorate the management of this disease, resulting in the discovery of many clinically approved small-molecule drugs for myeloid leukemia, including histone deacetylase inhibitors, hypomethylating agents, and tyrosine kinase inhibitors. This comprehensive review succinctly presents an up-to-date assessment of the application and synthetic routes of clinically sanctioned small-molecule drugs employed in the treatment of myeloid leukemia. Additionally, it provides a concise exploration of the pertinent challenges and prospects encompassing drug resistance and toxicity. Overall, this review effectively underscores the considerable promise exhibited by clinically endorsed small-molecule drugs in the therapeutic realm of myeloid leukemia, while concurrently shedding light on the prospective avenues that may shape the future landscape of drug development within this domain.

Recent advance of small-molecule drugs for clinical treatment of osteoporosis: A review.

Osteoporosis is a metabolic bone disorder typified by a reduction in bone mass and structural degradation of bone tissue, leading to heightened fragility and vulnerability to fractures. The incidence of osteoporosis increases with age, making it a significant public health challenge. The pathogenesis of osteoporosis involves an imbalance between osteoblast-mediated bone formation and resorption. The current treatment options for osteoporosis include bisphosphonates, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), and denosumab. The recent advances in small-molecule drugs for the clinical treatment of osteoporosis offer promising options for improving bone health and reducing fracture risk. This review aims to provide an overview of the clinical applications and synthetic routes of representative small-molecule drugs for the treatment of osteoporosis. A comprehensive understanding of the synthetic methods of drug molecules for osteoporosis may inspire the development of new, more effective, and practical synthetic techniques for treating this condition.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.