Caspase inhibitors: a review on recently patented compounds (2016-2023).

INTRODUCTION: Caspases are a family of protease enzymes that play a crucial role in apoptosis. Dysregulation of caspase activity has been implicated in various pathological conditions, making caspases an important focus of research in understanding cell death mechanisms and developing therapeutic strategies for diseases associated with abnormal apoptosis. AREAS COVERED: It is a comprehensive review of caspase inhibitors that have been comprising recently granted patents from 2016 to 2023. It includes peptide and non-peptide caspase inhibitors with their application for different diseases. EXPERT OPINION: This review categorizes and analyses recently patented caspase inhibitors on various diseases. Diseases linked to caspase dysregulation, including neurodegenerative disorders, and autoimmune conditions, are highlighted to accentuate the therapeutic relevance of the patented caspase inhibitors. This paper serves as a valuable resource for researchers, clinicians, and pharmaceutical developers seeking an up-to-date understanding of recently patented caspase inhibitors. The integration of recent patented compounds, structural insights, and mechanistic details provides a holistic view of the progress in caspase inhibitor research and its potential impact on addressing various diseases.

Expanding the Role of Chiral Drugs and Chiral Nanomaterials as a Potential Therapeutic Tool.

Chirality, the property of molecules having mirror-image forms, plays a crucial role in pharmaceutical and biomedical research. This review highlights its growing importance, emphasizing how chiral drugs and nanomaterials impact drug effectiveness, safety, and diagnostics. Chiral molecules serve as precise diagnostic tools, aiding in accurate disease detection through unique biomolecule interactions. The article extensively covers chiral drug applications in treating cardiovascular diseases, CNS disorders, local anesthesia, anti-inflammatories, antimicrobials, and anticancer drugs. Additionally, it explores the emerging field of chiral nanomaterials, highlighting their suitability for biomedical applications in diagnostics and therapeutics, enhancing medical treatments.

A comprehensive review on doxorubicin: mechanisms, toxicity, clinical trials, combination therapies and nanoformulations in breast cancer.

Doxorubicin is a key treatment for breast cancer, but its effectiveness often comes with significant side effects. Its actions include DNA intercalation, topoisomerase II inhibition, and reactive oxygen species generation, leading to DNA damage and cell death. However, it can also cause heart problems and low blood cell counts. Current trials aim to improve doxorubicin therapy by adjusting doses, using different administration methods, and combining it with targeted treatments or immunotherapy. Nanoformulations show promise in enhancing doxorubicin's effectiveness by improving drug delivery, reducing side effects, and overcoming drug resistance. This review summarizes recent progress and difficulties in using doxorubicin for breast cancer, highlighting its mechanisms, side effects, ongoing trials, and the potential impact of nanoformulations. Understanding these different aspects is crucial in optimizing doxorubicin's use and improving outcomes for breast cancer patients. This review examines the toxicity of doxorubicin, a drug used in breast cancer treatment, and discusses strategies to mitigate adverse effects, such as cardioprotective agents and liposomal formulations. It also discusses clinical trials evaluating doxorubicin-based regimens, the evolving landscape of combination therapies, and the potential of nanoformulations to optimize delivery and reduce systemic toxicity. The review also discusses the potential of liposomes, nanoparticles, and polymeric micelles to enhance drug accumulation within tumor tissues while sparing healthy organs.

Guanidinium-based Integrated Peptide Dendrimers: Pioneer Nanocarrier in Cancer Therapy.

The landscape of cancer therapy has witnessed a paradigm shift with the emergence of innovative delivery systems, and Guanidinium-based Peptide Dendrimers have emerged as a vanguard in this transformative journey. With their unique molecular architecture and intrinsic biocompatibility, these dendrimers offer a promising avenue for the targeted delivery of therapeutic cargo in cancer treatment. This comprehensive review delves into the intricate world of Guanidinium- based Peptide Dendrimers, unraveling their structural intricacies, mechanisms of action, and advancements that have propelled them from laboratory curiosities to potential clinical champions. Exploiting the potent properties of guanidinium, these dendrimers exhibit unparalleled precision in encapsulating and transporting diverse cargo molecules, ranging from conventional chemotherapeutics to cutting-edge nucleic acids. The review navigates the depths of their design principles, investigating their prowess in traversing the complex terrain of cellular barriers for optimal cargo delivery. Moreover, it delves into emerging trends, such as personalized therapeutic approaches, multimodal imaging, and bioinformatics-driven design, highlighting their potential to redefine the future of cancer therapy. Crucially, the review addresses the pivotal concerns of biocompatibility and safety, examining cytotoxicity profiles, immune responses, and in vivo studies. It underscores the importance of aligning scientific marvels with the stringent demands of clinical applications. Through each section, the narrative underscores the promises and possibilities that Guanidinium-based Peptide Dendrimers hold and how they can potentially reshape the landscape of precision cancer therapy.

Aptamer as a targeted approach towards treatment of breast cancer.

Aptamers, a novel type of targeted ligand used in drug delivery, have quickly gained popularity due to their high target specificity and affinity. Different aptamer-mediated drug delivery systems, such as aptamer-drug conjugate (ApDC), aptamer-siRNA, and aptamer-functionalised nanoparticle systems, are currently being developed for the successful treatment of cancer based on the excellent properties of aptamers. These systems can decrease potential toxicity and enhance therapeutic efficacy by targeting the drug moiety. In this review, we provide an overview of recent developments in aptamer-mediated delivery systems for cancer therapy, specifically for breast cancer, and talk about the potential applications and current issues of novel aptamer-based techniques. This study in aptamer technology for breast cancer therapy highlights key aptamers targeting well-established biomarkers such as HER2, oestrogen receptor, and progesterone receptor. Additionally, we explore the potential of aptamers in overcoming various challenges such as drug resistance and improving the delivery of therapeutic agents. This review aims to provide a deeper understanding of the present aptamer-based targeted delivery applications through in-depth analysis to increase efficacy and create new therapeutic approaches that may ultimately lead to better treatment outcomes for cancer patients.

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

Hydroxamic acid derivatives as selective HDAC3 inhibitors: computer-aided drug design strategies.

Histone deacetylases (HDACs) are critical epigenetic drug targets that have gained significant attention in the scientific community for the treatment of cancer. The currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Here, we describe our protocol for the discovery of novel potential hydroxamic acid based HDAC3 inhibitors through pharmacophore modeling, virtual screening, docking, molecular dynamics (MD) simulation and toxicity studies. The ten pharmacophore hypotheses were established, and their reliability was validated by different ROC (receiving operator curve) analysis. Among them, the best model (Hypothesis 9 or RRRA) was employed for searching SCHEMBL, ZINC and MolPort database to screen out hit molecules as selective HDAC3 inhibitors, followed by different docking stages. MD simulation (50 ns) and MMGBSA study were performed to study the stability of ligand binding modes and with the help of trajectory analysis, to calculate the ligand-receptor complex RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation) and H-bond distance, etc. Finally, in-silico toxicity studies were performed on top screened molecules and compared with reference drug SAHA and established structure-activity relationship (SAR). The results indicated that compound 31, with high inhibitory potency and less toxicity (probability value 0.418), is suitable for further experimental analysis.Communicated by Ramaswamy H. Sarma.

Pharmacophore modeling and virtual screening were performed with hydroxamic acid derivatives as HDAC3 inhibitors.MD simulation was performed for 50 ns time duration for selected protein-ligand complexes.SAR and toxicity studies (using TOPKAT tool) were performed.The results of these studies might be valuable in the further design and development of more potent HDAC3 inhibitors.

NOTCH Signaling Pathway: Occurrence, Mechanism, and NOTCH-Directed Therapy for the Management of Cancer.

It is now well understood that many signaling pathways are vital in carrying out and controlling essential pro-survival and pro-growth cellular functions. The NOTCH signaling pathway, a highly conserved evolutionary signaling pathway, has been thoroughly studied since the discovery of NOTCH phenotypes about 100 years ago in Drosophila melanogaster. Abnormal NOTCH signaling has been linked to the pathophysiology of several diseases, notably cancer. In tumorigenesis, NOTCH plays the role of a "double-edged sword," that is, it may act as an oncogene or as a tumor suppressor gene depending on the nature of the context. However, its involvement in several cancers and inhibition of the same provides targeted therapy for the management of cancer. The use of gamma (γ)-secretase inhibitors and monoclonal antibodies for cancer treatment involved NOTCH receptors inhibition, leading to the possibility of a targeted approach for cancer treatment. Likewise, several natural compounds, including curcumin, resveratrol, diallyl sulfide, and genistein, also play a dynamic role in the management of cancer by inhibition of NOTCH receptors. This review outlines the functions and structure of NOTCH receptors and their associated ligands with the mechanism of the signaling pathway. In addition, it also emphasizes the role of NOTCH-targeted nanomedicine in various cancer treatment strategies.

α-Tocopherol Polyethylene Glycol 1000 Succinate-Based Cationic Liposome for the Intracellular Delivery of Doxorubicin in MDA-MB-231 Triple-Negative Breast Cancer Cell Line.

Present research work reports the development of doxorubicin (DOX) loaded α-tocopherol polyethylene glycol 1000 succinate (TPGS)-coated cationic liposomes. The developed formulation was evaluated for its anticancer potential and intracellular uptake against the MDA-MB-231 breast cancer cell line. Moreover, hemocompatibility studies were also done on human blood red blood cells for the determination of blood compatibility. The prepared doxorubicin-loaded TPGS liposomes (DOX-LIPO-TPGS) and doxorubicin-loaded cationic liposomes (DOX-LIPO+-TPGS) reveal vesicle size (177.5 ± 2.5 and 201.7 ± 2.3 nm), polydispersity index (0.189 ± 0.01 and 0.218 ± 0.02), zeta potential (-36.9 ± 0.7 and 42 ± 0.9 mv), and % entrapment efficiency (65.88% ± 3.7% and 74.5% ± 3.9%). Furthermore, in vitro, drug release kinetics of the drug alone and drug from formulation shows sustained release behavior of developed formulation with 99.98% in 12 h and 80.98% release of the drug in 72 h, respectively. In addition, cytotoxicity studies and cellular DOX uptake on the MDA-MB-231 breast cancer cell line depict higher cytotoxic and drug uptake potential with better hemocompatibility of DOX-LIPO+-TPGS with respect to DOX. The data from the study revealed that TPGS plays an important role in enhancing the formulation's quality attributes like stability, drug release, cytotoxicity, and hemocompatibility behavior. This may serve that TPGS-coated cationic liposome as a vital candidate for the treatment of cancer and drug delivery in case of breast cancer.

Quality by design-assisted development of D-α-tocopherol polyethylene glycol 1000 succinate-incorporated gefitinib-loaded cationic liposome(s).

Aim: Gefitinib-loaded D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-coated cationic liposomes (GEF-TPGS-LIPO+) were developed and optimized by the quality by design (QbD) approach for its potential anticancer effect. Methods/materials: Box-Behnken design (BBD) a systematic design of experiments was added to screen and optimize the formulation variables. Results: GEF-TPGS-LIPO+ shows vesicle size (210 ± 4.82 nm), polydispersity index (0.271 ± 0.002), zeta potential (22.2 ± 0.84 mV) and entrapment efficiency (82.3 ± 1.95). MTT result shows the enhanced cytotoxicity and higher intracellular drug uptake with highest and lowest levels of the reactive oxygen species and NF-κB expressions on A549 lung cancer cells, determined by fluorescence-activated cell sorting flow cytometry. Conclusion: Potential anticancer effect on A549 cells might be found due to cationic liposomal interaction with cancer cells.

Multifunctional nanotherapeutics for intracellular trafficking of doxorubicin against breast cancer.

Aims: To develop an estrone-targeted d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)-based liposomal system for enhanced intracellular delivery of doxorubicin (DOX). Materials & methods: Zetasizer, transmission electron microscopy, energy dispersive x-ray, Fourier-transform infrared spectroscopy, differential scanning calorimetry, x-ray diffraction, confocal laser scanning microscopy and FACS analysis were used for formulation characterization and evaluation. Results: The DOX-LIPO-TPGS and DOX-LIPO-TPGS-estrone formulations had vesicle sizes (117.6 ± 3.51; 144 ± 5.00 nm), zeta potential (-36.4 ± 0.75; -35.8 ± 0.76), polydispersity index (0.123 ± 0.005; 0.169 ± 0.005) and percent entrapment efficiency (73.56 ± 3.55; 77.16 ± 3.83%) with improved cytotoxicity and cellular uptake, confirming the targeted potential of the developed formulations. Conclusion: The results suggest that the developed liposomal formulation with desired characteristics is potentially capable of nonimmunogenic, site-specific drug delivery to targeted cancer sites and reduced DOX-associated cardiac toxicity.

Doxorubicin (DOX) is an effective chemotherapy drug to treat breast cancer. However, DOX can cause unwanted side effects such as damage to the heart. This is due to side effects in healthy body tissues. This study was designed to develop nanoparticles that target cancer cells specifically to improve the delivery of DOX to these cells and prevent side effects elsewhere. Nanoparticles called liposomes were used as the platform for delivering DOX. Liposomes are sometimes coated with d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), a synthetic vitamin D derivative. This helps the liposome evade the immune system and release the drug more effectively. TPGS was tethered with estrone (ES), a type of estrogen. Certain breast cancer cells have many more estrogen receptors on their cell surface than healthy cells. TPGS-ES was coated on DOX-loaded liposomes to achieve enhanced intracellular delivery of DOX to breast cancer cells specifically. These liposomes were called DOX-LIPO-TPGS-ES. This liposome proved more toxic to cells in a breast cancer cell line than free DOX or liposomes without tethered ES. When tested in rats, DOX-LIPO-TPGS-ES showed increased tumor uptake compared with free DOX or liposomes without tethered ES. Rats treated with either liposomal drug showed normal levels of key markers associated with heart function, whereas those treated with free DOX showed increased levels of these markers. These results suggest that DOX-LIPO-TPGS-ES is capable of highly targeted delivery of DOX with limited side effects.

Emerging targeted therapeutic strategies for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), has clinical features including a high degree of invasiveness, an elevated risk of metastasis, tendency to relapse, and poor prognosis. It constitutes around 10-15% of all breast cancer, and having heredity of BRCA1 mutated breast cancer could be a reason for the occurrence of TNBC in women. Overexpression of cellular and molecular targets, i.e. CD44 receptor, EGFR receptor, Folate receptor, Transferrin receptor, VEGF receptor, and Androgen receptor, have emerged as promising targets for treating TNBC. Signalling pathways such as Notch signalling and PI3K/AKT/mTOR also play a significant role in carrying out and managing crucial pro-survival and pro-growth cellular processes that can be utilised for targeted therapy against triple-negative breast cancer. This review sheds light on various targeting strategies, including cellular and molecular targets, signalling pathways, poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors PARP, immunotherapy, ADCs have all found a place in the current TNBC therapeutic paradigm. The role of photothermal therapy (PTT) and photodynamic therapy (PDT) has also been explored briefly.

A short appraisal of polylactic-co-glycolic acid based polymer nanotechnology for colon cancer: recent advances and literature evidences.

The currently available formulations provided non-targeted treatment of colon cancer, the deadliest cancer variant. Due to biopharmaceutical hindrances, the majority of the drugs are unable to reach the target site. Polylactic-co-glycolic acid (PLGA) is one of the versatile polymers in cancer treatment, diagnostics and theranostics. The unique mechanism of surface modifications in PLGA properties in colon cancer has been a keen interest to be used in different nanoparticles for improving biopharmaceutical attributes. The ongoing use of these smart nano-carriers has allowed targeted delivery of several active components on a wide scale. The main goal of this review is to compile information on PLGA-based nanocarriers which possess several desirable properties for drug delivery applications, including biocompatibility, biodegradability and tunable drug-release kinetics.

Current progress in the targeted therapy of breast cancer: Structure-activity correlation and docking studies (2015-2021).

Despite cancer research and therapy, breast cancer remains a complicated health crisis in women and represents a top biomedical research priority. Nowadays, breast cancer is an extremely heterogeneous disease and is known as the leading cause of death among women worldwide. The incidence and mortality rates of breast cancer have been increasing gradually for the past decades. Nowadays, common treatments for breast cancer are chemotherapy, endocrine therapy, immunotherapy, radiotherapy, and surgery. The most common targets in breast cancer treatment are human epidermal growth factor receptor 2 (HER2) and estrogen receptors. The literature suggests that several targets/pathways are also involved in the development of breast cancer, that is, poly(ADP-ribose) polymerase (PARP), bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/6), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), polo-like kinase 1 (PLK1), phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), histone deacetylase (HDAC), nuclear factor kappa B (NF-κB), PD-L1, and aromatase inhibitors. Meanwhile, the study of breast cancer is a hot topic in the current scenario of basic/clinical research. This review article provides information on different targets associated with breast cancer and summarizes the progress of current research on synthesized inhibitors as anti-breast cancer agents from 2015 to 2021. The review aims to provide structure-activity relationship and docking studies for designing novel compounds for breast cancer therapy.

Current Medicinal Insights on Synthetic Small Molecules and Natural Origin Products as PD-1/PD-L1 Inhibitors.

Cancer is one of the leading causes of death worldwide. Each year, millions of people are diagnosed with cancer; hence, researchers have always been curious and busy developing cancer treatments. Despite thousands of studies, cancer is still a major threat to human beings. One of the mechanisms through which cancer invades a human being is the immune escape mechanism, which has been the focus of studies in the past years. PD-1/PD-L1 pathway plays a major role in this immune escape. Therefore, research focusing on blocking this pathway has led to the discovery of molecules based on monoclonal antibodies that work quite well, but despite the successful application of monoclonal antibodies as inhibitors of the PD-1/PD-L1 pathway, there are some drawbacks, such as poor bioavailability and several immune-related adverse effects, which have led the researchers toward further investigation, thereby resulting in the discovery of different types of molecules, such as small molecule inhibitors, PROTAC-based molecules, and naturally derived peptide molecules that function as inhibitors of the PD-1/PD-L1 pathway. Here, in this review, we have summarized recent findings of these molecules and focused on their structural activity relationship. The development of these molecules has opened more prospects in cancer therapy.

Doxorubicin Conjugates: An Efficient Approach for Enhanced Therapeutic Efficacy with Reduced Side Effects.

Continuous drug delivery modification is the scientific approach and is a basic need for the efficient therapeutic efficacy of active drug molecules. Polymer-drug conjugates have long been a hallmark of the drug delivery sector, with various conjugates on the market or in clinical trials. Improved drug solubilization, extended blood circulation, decreased immunogenicity, controlled release behavior, and increased safety are the advantages of conjugating drugs to the polymeric carrier like polyethylene glycol (PEG). Polymer therapies have evolved over the last decade, resulting in polymer-drug conjugates with diverse topologies and chemical properties. Traditional nondegradable polymeric carriers like PEG and hydroxy propyl methacrylate have been clinically employed to fabricate polymer-drug conjugates. Still, functionalized polymer-drug conjugates are increasingly being used to increase localized drug delivery and ease of removal. Researchers have developed multifunctional carriers that can "see and treat" patients using medicinal and diagnostic chemicals. This review focused on the various conjugation approaches for attaching the doxorubicin to different polymers to achieve enhanced therapeutic efficacy, that is, increased bioavailability and reduced adverse effects.

Solid Lipid Nanoparticles (SLNs): Advancements in Modification Strategies Toward Drug Delivery Vehicle.

Solid lipid nanoparticles are at the cornerstone of the swiftly growing area of medical nanotechnology, having several potential functions in drug delivery, research, clinical care, and a variety of other fields. They provide the opportunity of developing novel therapies due to their unique properties, such as small particle size and being prepared from physiological biodegradable lipids. The loading of bioactive molecules into nanocarriers is a novel drug delivery prototype employed for various drug targeting levels. Hence, SLNs hold a great promise for achieving the aim of targeted and controlled drug delivery. For this reason, they have attracted the extensive attention of scientists and researchers. This review is based on recent studies and research, and here we present advantages, disadvantages, and preparation methods, several advanced modifications, targeting strategies, and recent applications of solid lipid nanocarriers in drug delivery systems.

Potential role of resveratrol and its nano-formulation as anti-cancer agent.

The uncontrolled and metastatic nature of cancer makes it worse and more unpredictable. Hence, many therapy and medication are used to control and treat cancer. However, apart from this, many medications cause various side effects. In America, nearly 8% of patients admitted to the hospital are due to side effects. Cancer is more seen in people residing in developed countries related of their lifestyle. There are various phytoconstituents molecules in which resveratrol (RSV) is the best-fitted molecule for cancer due to its significantly less adverse effect on the body. RSV inhibits the initiation and progression of cell proliferation due to the modulation of various pathways like the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. RSV downgraded cell cycle-regulated proteins like cyclin E, cyclin D1, and proliferating cell nuclear antigen (PCNA) and induced the release of cytochrome c from the mitochondria, causing apoptosis or programmed cell death (PCD). A great benefit comes with some challenges, hence, RSV does suffer from poor solubility in water i.e. 0.05 mg/mL. It suffers from poor bioavailability due to being highly metabolized by the liver and intestine. Surprisingly, RSV metabolites also induce the metabolism of RSV. Hence, significantly less amount of RSV presented in the urine in the unchanged form. Due to some challenges like poor bioavailability, less aqueous solubility, and retention time in the body, researchers concluded to make the nanocarriers for better delivery. Adopting the technique of nano-formulations, increased topical penetration by up to 21%, improved nano-encapsulation and consequently improved bioavailability and permeability by many folds. Hence, the present review describes the complete profile of RSV and its nano-formulations for improving anti-cancer activity along with a patent survey.

Recent Progress in Histone Deacetylase (HDAC) 1 Inhibitors as Anticancer Agent.

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. HDAC1 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC1 displays a unique structure primarily found in the nucleus and involved in epigenetic and transcriptional regulation. HDAC1 is ubiquitously expressed and associated with Sin3, NuRD, and CoRest transcription repressive complexes responsible for distinct cellular processes like cell proliferation and survival. HDAC1 inhibitors have been effectively used to treat various cancers such as gastric, breast, colorectal, prostate, colon, lung, ovarian, pancreatic, and inflammation without exerting significant toxic effects. In this review, we summarize four major structural classes of HDAC1 inhibitors (i.e., hydroxamic acid derivatives, benzamides, hydrazides, and thiols) with their structural activity relationship. This review is a comprehensive work on HDAC1 inhibitors to achieve deep insight of knowledge about the structural information of HDAC1 inhibitors. It may provide up-to-date direction for developing new selective HDAC1 inhibitors as anticancer agents.