Due to the complicated pathogenesis of Alzheimer's disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3β (GSK-3β) plays a vital role in the AD pathological process. In this study, we discovered a novel 1H-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3β inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3β with an IC 50 of 66 ± 2.5 nM. At the concentration of 20 µM, B10 increased β-catenin abundance (β-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3β at Ser9 (p-GSK-3β/GAPDH: 0.53 ± 0.045 vs. 0.35 ± 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 ± 0.065 vs. 0.83 ± 0.061) in SH-SY5Y cells. Unlike other GSK-3β inhibitors, B10 had a direct effect on Aβ by inhibiting Aβ 1-42 aggregation and promoting the Aβ 1-42 aggregate disassociation. It selectively chelated with Cu 2+ , Zn 2+ , Fe 3+, and Al 3+ , and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3β and β-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3β inhibitor that has a direct on Aβ and serves as a multifunctional anti-AD agent for further investigations.Cells 2020, 9, 649 2 of 15 Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase largely expressed in the central nervous system (CNS), plays important roles in metabolism, proliferation, and apoptosis [24]. The two subtypes, GSK-3α (51 kDa) and GSK-3β (47 kDa), are 98% identical in their respective catalytic domains [25]. GSK-3β is predominantly the main isoform in most brain areas and the key kinase in AD responsible for the abnormal hyperphosphorylation of the microtubule-associated tau protein [26][27][28]. The hyperphosphorylated tau impairs the interaction between tau proteins and microtubules, leading to the detachment of tau from microtubules, destabilizing the microtubules in the neurons. The accumulation of hyperphosphorylated tau further generates paired helical filaments and subsequent aggregates to form the intracellular NFTs, one important biomarker of AD [29][30][31]. Moreover, increased GSK-3β activity may induce Aβ formation through its regulation of γ-secretase in the cleavage of the amyloid-precursor protein (APP) [32]. Overactivation of GSK-3β is also involved in neuroinflammation, neuronal death, and apoptosis through cell signal pathways [33,34]. Both in AD model and preclinical and clinical studies, GSK-3β has been proven as a therapeutic target for AD [35][36][37][38].In an effort to find potent GSK-3β inhibitors to target multifacets of AD [39], we report here a unique and potent GSK-3β inhibitor, 6-(5-(4-((pyridin-4-ylamino)methyl)phenyl)-1H-pyrrolo[2,3-b] pyridin-3-yl)quinolin-8-ol (B10), which has a direct effect on Aβ targets tau an...
Background: The casein kinase 1 (CK1) family are involved in regulating many cellular processes including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms especially CK1δ and CK1ε have emerged as important therapeutic target for severe disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors. Method: Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion on those published as patents. Results: This review presents the current state of knowledge on the development of CK1 inhibitors, including both the synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships. Conclusion: Thorough physicochemical characterization and biological investigations, it is possible to understand structureactivity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.
Background: Microtubule targeting agents (MTAs) represent the most successful anticancer drugs for cancer chemotherapy. Through interfering with the tubulin polymerization and depolymerization dynamics, MTAs influence intracellular transport and cell signal pathways, inhibit cell mitosis and cell proliferation, and induce cell apoptosis and death. The tubulin maytansine site binding agents are natural or nature-derived products that represent one type of the MTAs that inhibit tubulin polymerization and exhibit potent antitumor activity both in vitro and in vivo. They are used as antibody-drug conjugates (ADCs) in cancer chemotherapy. Method: Using SciFinder® as a tool, the publications about maytansine, its derivatives, maytansine binding site, maytansine site binding agents and their applications as MTAs for cancer therapy were surveyed with an exclusion on those published as patents. The latest progresses in clinical trials were obtained from the clinical trial web. Results: This article presents an introduction about MTAs, maytansine, maytansine binding site and its ligands, the applications of these ligands as MTAs and ADCs in cancer therapy. Conclusion: The maytansine site binding agents are powerful MTAs for cancer chemotherapy. The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy.
The epigenetic reader BRD4 is involved in chromatin remodelling and transcriptional regulation, making it a promising therapeutic target. However, over the past decades, many BRD4 inhibitors that entered clinical trials were, in the main, unsatisfactory, due to some therapeutic limitations such as offtarget effects and drug resistance. Combining a BRD4 inhibitor with another drug was expected to be an ideal option to overcome these hurdles and to improve therapeutic outcomes. However, such combination therapy could trigger toxicity caused by drug-drug interactions, complex pharmacokinetics, and additive effects. Recently, the application of dual-target drugs targeting BRD4 and other kinases has become an attractive approach to remedy the defects of a single BRD4 inhibitor. This review focuses on recent advances in the discovery of dual BRD4-kinase inhibitors, with an emphasis on their co-crystal structures and structure-activity relationships (SARs), as well as future perspectives in this field.
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