Benzimidazole‐oxindole hybrids: A novel class of selective dual CDK2 and GSK‐3β inhibitors of potent anticancer activity DOI
Heba T. Abdel‐Mohsen, Yasmin M. Syam,

Mahmoud S. Abd El‐Ghany

et al.

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(10)

Published: July 23, 2024

Abstract A new series of benzimidazole‐oxindole hybrids 8a–x was discovered as dual cyclin‐dependent kinase (CDK2) and glycogen synthase kinase‐3‐beta (GSK‐3β) inhibitors with potent anticancer activity. The synthesized hits displayed activity against national cancer institute cell lines in single‐dose five‐dose assays. Moreover, the derivatives 8k , 8l 8n, 8o 8p demonstrated cytotoxic PANC‐1 cells IC 50 = 1.88–2.79 µM. In addition, 8n antiproliferative on MG‐63 line (IC 0.99–1.90 µM). Concurrently, hybrid 8v exhibited CDK2/GSK‐3β inhibitory values 0.04 0.021 µM, respectively. more than 10‐fold higher selectivity toward CDK2 GSK‐3 β over CDK1, CDK5, GSK‐3α, vascular endothelial growth factor receptor‐2, B‐rapidly accelerated fibrosarcoma. Screening effect cycle apoptosis their ability to arrest at G2‐M phase potentiate both lines. silico docking into catalytic pocket GSK‐3β revealed its perfect fitting through formation hydrogen bonding hydrophobic interactions key amino acids binding sites. absorption, distribution, metabolism, excretion studies proved that exhibit satisfactory drug‐likeness properties for drug development.

Language: Английский

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer DOI Creative Commons
Antonino Glaviano, Aaron Song Chuan Foo, Hiu Yan Lam

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Aug. 18, 2023

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Growth factor signalling to transcription factors the PAM axis regulated by multiple cross-interactions with several other pathways, dysregulation of can predispose cancer development. most frequently activated human often implicated resistance anticancer therapies. Dysfunction components this such as hyperactivity PI3K, loss function PTEN, gain-of-function AKT, are notorious drivers treatment disease progression cancer. In review we highlight major dysregulations cancer, discuss results AKT mTOR inhibitors monotherapy co-administation antineoplastic agents clinical trials strategy for overcoming resistance. Finally, mechanisms targeted therapies, including immunology immunotherapies also discussed.

Language: Английский

Citations

823
Wnt/β-catenin signaling in cancers and targeted therapies DOI Creative Commons
Fanyuan Yu, Changhao Yu, Feifei Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 30, 2021

Abstract Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation is tightly linked with the increment prevalence, advancement malignant progression, development poor prognostics, even ascendence cancer-associated mortality. Early investigations have proposed theoretical potential that efficient repression this might provide promising therapeutic choices managing various types cancers. Up to date, many therapies targeting developed, which assumed endow clinicians new opportunities developing more satisfactory precise remedies for patients aberrant signaling. However, current facts indicate clinical translations signaling-dependent targeted faced un-neglectable crises challenges. Therefore, study, we systematically reviewed most updated knowledge relatively generate a clearer accurate awareness both developmental stage underlying limitations Wnt/β-catenin-targeted Insights study will help readers better understand roles insights acknowledge challenges

Language: Английский

Citations

438
The Role of Oxidative Stress and Its Counteractive Utility in Colorectal Cancer (CRC) DOI Open Access

Debasish Basak,

Mohammad N. Uddin,

Jake Hancock

et al.

Cancers, Journal Year: 2020, Volume and Issue: 12(11), P. 3336 - 3336

Published: Nov. 11, 2020

An altered redox status accompanied by an elevated generation of reactive oxygen/nitrogen species (ROS/RNS) has been implicated in a number diseases including colorectal cancer (CRC). CRC, being one the most common cancers worldwide, reported to be associated with multiple environmental and lifestyle factors (e.g., dietary habits, obesity, physical inactivity) harboring heightened oxidative stress that results genomic instability. Although under normal condition ROS regulate many signal transduction pathways cell proliferation survival, overwhelming antioxidant capacity due metabolic abnormalities oncogenic signaling leads adaptation response imparts drug resistance. Nevertheless, excessive reliance on production makes tumor cells increasingly vulnerable further insults, abolition such resistance through perturbation could instrumental preferentially eliminate them. The goal this review is demonstrate evidence links development CRC assimilate up-to-date information would facilitate future investigation CRC-associated biology. Concomitantly, we argue exploitation distinct biochemical property might offer fresh avenue effectively eradicate these cells.

Language: Английский

Citations

153
Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases DOI
Li Wang, Jiajia Li,

Li‐jun Di

et al.

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(2), P. 946 - 982

Published: Nov. 3, 2021

Abstract Glycogen synthase kinase‐3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen (GS) in response to insulin stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms GSK3, GSK3α, GSK3β, have been implicated many biological pathophysiological processes. The various functions are indicated by its widespread distribution multiple cell types tissues. studies activity using animal models the observed effects GSK3‐specific inhibitors provide more insights into roles regulating cross‐talk between some important regulators sensors mitochondrial component function further highlight molecular mechanisms involved regulate metabolic activity, beyond classical regulatory effect on GS. In this review, we summarize specific tissues tightly associated with development disorders. We also address impacts function, regulation. application clinical tests will be highlighted too. Interactions GSK3‐mediated responses different stresses related described brief overview previously less‐appreciated diseases through GS other functions.

Language: Английский

Citations

130
A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies DOI
Riya Thapa, Gaurav Gupta, Asif Ahmad Bhat

et al.

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 253, P. 127375 - 127375

Published: Oct. 13, 2023

Language: Английский

Citations

89
MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products DOI Creative Commons

Ka Iong Chan,

Siyuan Zhang, Guodong Li

et al.

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(2), P. 640 - 640

Published: Jan. 1, 2024

Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing clinical trials shown that sustained tumor volume reduction can be achieved when MYC is inactivated, different combinations of therapeutic agents inhibitors are currently being developed. In this review, we first provide a summary multiple biological functions oncoprotein in cancer treatment, highlighting equilibrium points MYC/MAX, MIZ1/MYC/MAX, MAD (MNT)/MAX complexes further potential treatment could used restrain oncogene expression its tumorigenesis. We also discuss multifunctional capacity various cellular processes, influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, intestinal flora. Moreover, summarize therapy patent landscape emphasize as druggable target, using herbal medicine modulators. Finally, describe pending challenges future perspectives biomedical research, involving development approaches modulate or targeted genes. Patients with cancers driven by signaling may benefit from therapies targeting these pathways, which delay cancerous growth recover antitumor responses.

Language: Английский

Citations

21
Glycogen Synthase Kinase 3β in Cancer Biology and Treatment DOI Creative Commons
Takahiro Domoto, Masahiro Uehara,

Dilireba Bolidong

et al.

Cells, Journal Year: 2020, Volume and Issue: 9(6), P. 1388 - 1388

Published: June 3, 2020

Glycogen synthase kinase (GSK)3β is a multifunctional serine/threonine protein with more than 100 substrates and interacting molecules. GSK3β normally active in cells negative regulation of activity via phosphorylation its serine 9 residue required for most normal to maintain homeostasis. Aberrant expression contributes the pathogenesis progression common recalcitrant diseases such as glucose intolerance, neurodegenerative disorders cancer. Despite recognized roles against several proto-oncoproteins mediators epithelial–mesenchymal transition, deregulated also participates tumor cell survival, evasion apoptosis, proliferation invasion, well sustaining cancer stemness inducing therapy resistance. A therapeutic effect from inhibition has been demonstrated 25 different types. Moreover, there increasing evidence that protects tissues harmful effects associated conventional therapies. Here, we review supporting aberrant hallmark property highlight beneficial on during therapy. The biological rationale targeting treatment discussed at length.

Language: Английский

Citations

90
Lithium and Therapeutic Targeting of GSK-3 DOI Creative Commons

Melinda Snitow,

Rahul S. Bhansali, Peter S. Klein

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(2), P. 255 - 255

Published: Jan. 28, 2021

Lithium salts have been in the therapeutic toolbox for better or worse since 19th century, with purported benefit gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, remarkable effects of reported by John Cade subsequently Mogens Schou revolutionized treatment bipolar disorder. The known molecular targets are surprisingly few include signaling kinase glycogen synthase kinase-3 (GSK-3), a group structurally related phosphomonoesterases includes inositol monophosphatases, phosphoglucomutase. Here we present brief history uses then focus on GSK-3 as target diverse diseases, including disorder, cancer, coronavirus infections.

Language: Английский

Citations

88
DYRK1A inhibitors for disease therapy: Current status and perspectives DOI
Tong Liu, Yuxi Wang, Jiaxing Wang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 229, P. 114062 - 114062

Published: Dec. 21, 2021

Language: Английский

Citations

79
Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery? DOI Creative Commons
Angela De Simone, Vincenzo Tumiatti, Vincenza Andrisano

et al.

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 64(1), P. 26 - 41

Published: Dec. 21, 2020

Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown different physiological networks. As result, several lines evidence suggest that it could be more efficiently tackled by molecules directed toward dysregulated biochemical targets or pathways. In this context, selection to which new will crucial. For years, design such multitarget-directed ligands (MTDLs) has been based on main involved in "cholinergic" and "β-amyloid" hypothesis. Recently, there have some reports MTDLs targeting glycogen synthase kinase 3β (GSK-3β) enzyme, due its appealing properties. Indeed, enzyme tau hyperphosphorylation, controls multitude CNS-specific signaling pathways, establishes strict connections with factors implicated AD pathogenesis. present Miniperspective, we discuss reasons behind development GSK-3β-directed highlight recent efforts obtain these classes as potential disease-modifying agents.

Language: Английский

Citations

73