In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a-h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3β inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3β inhibitory activity with IC50 of 0.244 and 0.128 μM, respectively, against CDK2, and IC50 of 0.317 and 0.160 μM, respectively, against GSK-3β. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3β downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and β-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3β in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells\' progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.

Growing evidence has shown that hypovitaminosis D is a risk factor for developing schizophrenia and comorbid conditions. Therefore, this study aimed to examine the effect of vitamin D supplementation on serum levels of vitamin D, metabolic factors related to insulin resistance (IR) and the severity of the disorder in patients with schizophrenia.
Forty-eight chronic male patients with schizophrenia with vitamin D deficiency (≤20 ng/mL= (≤50 nmol/l) were selected and randomly assigned to vitamin D treatment and placebo groups. Subjects were supplemented for 8 weeks with vitamin D (2000 IU/day) or placebo.
Within-group comparison revealed that the vitamin D group had a significant reduction in waist circumference, Positive and Negative Syndrome Scale - total score (PANSS-TS), and glycogen synthase kinase 3 beta (GSK-3β) levels (P = .022, P = <.001 and P = .013, respectively). On the other hand, the placebo group showed a significant increase in the level of fasting serum insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P = .003 and P = .003). The between-group comparison showed a significant difference in terms of PANSS-TS, GSK-3β, fasting serum insulin (FSI), and HOMA-IR (P = .022, P = .048, P = .013 and P = .014 respectively).
Among vitamin D deficient patients with schizophrenia, vitamin D supplementation may affect GSK-3 β, an important biomarker in schizophrenia and insulin resistance. In addition, vitamin D supplementation in such patients may reduce the disorder\'s symptom severity.

UNASSIGNED: GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect.
UNASSIGNED: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety.
UNASSIGNED: RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30-69) years; 6 female, 12 male; median ECOG 1 (0-2); median recurrences 3 (1-6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4-305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%.
UNASSIGNED: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy.
Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained.
AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments.
AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.

The global impact of Alzheimer\'s disease (AD) necessitates intensive research to find appropriate and effective drugs. Many studies in AD suggested beta-amyloid plaques and neurofibrillary tangles-associated tau protein as the key targets for drug development. On the other hand, it is proved that triggering of Glycogen Synthase Kinase-3β (GSK-3β) also cause AD, therefore, GSK-3β is a potential drug target to combat AD. We, in this study, investigated the ability of small molecules to inhibit GSK-3β through virtual screening, Absorption, Distribution, Metabolism, and Excretion (ADME), induced-fit docking (IFD), molecular dynamics simulation, and binding free energy calculation. Besides, molecular docking was performed to reveal the binding and interaction of the ligand at the active site of GSK-3β. We found two compounds such as 6961 and 6966, which exhibited steady-state interaction with GSK-3β for 30 ns in molecular dynamics simulation. The compounds (6961 and 6966) also achieved a docking score of -9.05 kcal/mol and -8.11 kcal/mol, respectively, which is relatively higher than the GSK-3β II inhibitor (-6.73 kcal/mol). The molecular dynamics simulation revealed that the compounds have a stable state during overall simulation time, and lesser root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) values compared with co-crystal. In conclusion, we suggest the two compounds (6966 and 6961) as potential leads that could be utilized as effective inhibitors of GSK-3β to combat AD. Communicated by Ramaswamy H. Sarma.

The Wnt pathway is the most important cascade in the nervous system; evidence has indicated that deregulation of the Wnt pathway induced pathogenic hallmarks of neurodegenerative diseases. Glycogen synthase kinase-3β (GSK-3β) as the main member of the Wnt pathway increases tau inclusions, the main marker in the neurodegenerative diseases. Phosphorylated tau is observed in the pre-tangle of the neurons in the early stage of neurodegenerative diseases. The researchers always try to improve pharmacological approaches of new therapeutic strategies to the treatment of neurodegenerative diseases that are required to represent a significant entry point by understanding the theoretical interactions of the molecular pathways. In this review, we have discussed the recent knowledge about the canonical and non-canonical Wnt signalling pathway, GSK-3β, Wnt/β-catenin antagonists, tau phosphorylation, and their important roles in the neurodegenerative diseases.

The enzyme Glycogen Synthase Kinase 3-β (GSK-3β) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer\'s Disease (AD).
In this work, we performed a molecular modeling study of existing GSK-3β inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability.
In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3β, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability.
It is concluded that the analogues of GSK-3β inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment.

A good understanding of the inhibition mechanism of enzymes exhibiting high levels of similarity is the first step to the discovery of new drugs with selective potential. Examples of such proteins include glycogen synthase kinase-3 (GSK-3β) and cyclin-dependent kinase 2 (CDK-2). This article reports the mechanism of such enzyme inhibition as analyzed by an indoline sulfamylophenyl derivative (CHEMBL410072). Previous work has shown that such compounds exhibit selective properties towards their biological targets. This study used a combined procedure involving docking and molecular dynamics simulations, which allowed identification of interactions responsible for stabilization of complexes, and analysis of the dynamic stability of the systems obtained. The initial data obtained during the molecular docking stage show that the ligand molecule exhibits a similar affinity towards both active sites, which was confirmed by quantification of identified interactions and energy values. However, the data do not cover dynamic aspects of the considered systems. Molecular dynamics simulations realized for both complexes indicate significant dissimilarities in dynamics properties of both side chains of the considered ligands, especially in the case of the part containing the sulfamide group. Such increased mobility of the analyzed systems disrupts the stability of binding in the stabilized complex with GSK-3β protein, which finally affects also the binding affinity of the ligand molecule towards this enzyme.

Alzheimer\'s disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer\'s disease remain limited. The multifactorial nature of Alzheimer\'s disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer\'s disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer\'s disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against Aβ25-35- induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer\'s disease treatment.

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