Drugs that function through allosteric inhibition of kinase signaling represent a promising approach for the targeted discovery of therapeutics. The majority of developed allosteric kinase inhibitors ...are characterized as type III and IV inhibitors that show good kinome selectivity but generally lack the subtype selectivity of same kinase family. Recently allosteric inhibitors have been developed that bind outside the catalytic kinase domain with high selectivity for specific kinase subtypes. Allosteric inhibitors that bind to the pseudokinase domain of pseudokinase or the extracellular domain of receptor tyrosine kinases are reviewed. We also review recent developments in the field of allosteric kinase inhibitors including examples of proteolysis targeting chimeras, and highlight the unique binding modes for each type of inhibitors and address future opportunities in this area.
Allosteric inhibition of kinase signaling is a promising approach for the targeted discovery of therapeutics with exceptional selectivity and the ability of overcoming the acquired resistance of the orthosteric ATP‐binding site inhibitors. The recent developments of allosteric kinase inhibitors that bind outside the catalytic kinase domain further warrant considerable interest and offer unique opportunities in this area.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•β-Hydroxybutyrate within its physiological range promotes BDNF expression in neurons under adequate glucose supply.•β-Hydroxybutyrate induces BDNF expression by activating cAMP/PKA/p-CREB ...signaling.•β-Hydroxybutyrate regulates the epigenetic markers of H3K27ac and H3K27me3 binding at Bdnf promoters.•β-Hydroxybutyrate enhances H3K27ac level independent on HDAC.
Neurobiological evidence suggests that the ketone metabolite β-hydroxybutyrate (BHBA) exerts many neuroprotective functions for the brain. The previous study revealed that BHBA could promote the expression of brain-derived neurotrophic factor (BDNF) at glucose inadequate condition. Here we demonstrated that BHBA administration induced the expression of BDNF in the hippocampus of mice fed with normal diet. In vitro experiment results also showed that 0.02–2 mM BHBA significantly increased BDNF expression in both the primary hippocampal neurons and the hippocampus neuron cell line HT22 under adequate glucose supply. Bdnf transcription induced by BHBA stimulus was mediated through the cAMP/PKA-triggered phosphorylation of CREB (S133) and the subsequent up-regulation of histone H3 Lysine 27 acetylation (H3K27ac) binding at Bdnf promoters I, II, IV, and VI. Moreover, BHBA stimulus induced a decrease in tri-methylation of H3K27 (H3K27me3) binding at the Bdnf promoters II and VI and the elevation of H3K27me3-specific demethylase JMJD3, which also contributed to the activation of Bdnf transcription. These results demonstrated that BHBA within the physiological range could promote BDNF expression in neurons via a novel signaling function. Moreover, BHBA might possess more broad epigenetic regulatory activities, which affected both the acetylation and demethylation of H3K27. Our findings reinforce the beneficial effect of BHBA on the central nervous system (CNS) and suggest that BHBA administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
► TFPL possesses considerable amounts of flavonoids. ► TFPL possess potent antioxidant and free radical scavenging activities. ► Protect effect of TFPL on cell viability and antioxidative status in ...MC3T3-E1 cells.
Persimmon leaves are commonly consumed as beverages, but are also used as a popular folk medicine in China. The purpose of this work is to assess the antioxidant activity of an extract of total flavonoids from persimmon leaves (TFPL). The effect of TFPL on total antioxidant activity, reducing power, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, superoxide anion (O2-) radical scavenging, hydroxyl (OH) radical scavenging and metal chelating activities was examined. We found that TFPL possesses considerable amounts of flavonoids (192μg catechin equivalent/g of extract). The effect of this extract in total antioxidant activity, scavenging activity of superoxide anion and hydroxyl radical, reducing power and iron chelating activity was significantly better than that of rutin. However, the effect of TFPL in free radical scavenging of DPPH was significantly not as good as than rutin. In addition, TFPL significantly decreased the level of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in MC3T3-E1 cells in a dose-dependent manner. In conclusion, TFPL possess potent antioxidant and free radical scavenging activities. These antioxidant activities could contribute, at least in part, to the traditionally claimed therapeutic benefits of persimmon leaves.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Both the first‐generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second‐generation covalent epidermal growth factor receptor tyrosine kinase ...inhibitor (EGFR‐TKI) afatinib have significantly improved the survival of non‐small‐cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to the clinically acquired resistance to the first‐ and second‐generation EGFR‐TKIs drugs. A number of the third‐generation wild‐type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFRT790M. More recently, a tertiary EGFRC797S mutation was reported as the dominant resistance mechanism to the third‐generation irreversible inhibitors. It is highly desirable to develop the fourth‐generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third‐ and fourth‐generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFRC797S mutation.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Background Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was ...thoroughly investigated for its expression and functions in breast cancer. Methods Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Results Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. Conclusion ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.
Neurotrophic receptor kinase (
) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive ...therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKA
, homologous TRKC
) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acetyl-CoA is a fundamental metabolite for all life on Earth, and is also a key starting point for the biosynthesis of a variety of industrial chemicals and natural products. Here we design and ...construct a Synthetic Acetyl-CoA (SACA) pathway by repurposing glycolaldehyde synthase and acetyl-phosphate synthase. First, we design and engineer glycolaldehyde synthase to improve catalytic activity more than 70-fold, to condense two molecules of formaldehyde into one glycolaldehyde. Second, we repurpose a phosphoketolase to convert glycolaldehyde into acetyl-phosphate. We demonstrated the feasibility of the SACA pathway in vitro, achieving a carbon yield ~50%, and confirmed the SACA pathway by
C-labeled metabolites. Finally, the SACA pathway was verified by cell growth using glycolaldehyde, formaldehyde and methanol as supplemental carbon source. The SACA pathway is proved to be the shortest, ATP-independent, carbon-conserving and oxygen-insensitive pathway for acetyl-CoA biosynthesis, opening possibilities for producing acetyl-CoA-derived chemicals from one-carbon resources in the future.
Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth ...factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.
The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological ...effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.1 sub-THz radiation can modulate the immune system and alleviate symptoms of arthritis in collagen-induced arthritis (CIA) mice through a nonthermal manner. The application of 0.1 sub-THz irradiation led to a decrease in proinflammatory factors within the joints and serum, reducing the levels of blood immune cells and the quantity of splenic CD4+ T cells. Notably, 0.1 sub-THz irradiation restored depleted Treg cells in CIA mice and re-established the Th17/Treg equilibrium. These findings suggested that sub-THz irradiation plays a crucial role in systemic immunoregulation. Further exploration of its immune modulation mechanisms revealed the anti-inflammatory properties of 0.1 sub-THz on LPS-stimulated skin keratinocytes. Through the reduction in NF-κB signaling and NLRP3 inflammasome activation, 0.1 sub-THz irradiation effectively decreased the production of inflammatory factors and immune-active substances, including IL-1β and PGE2, in HaCaT cells. Consequently, 0.1 sub-THz irradiation mitigated the inflammatory response and contributed to the maintenance of immune tolerance in CIA mice. This research provided significant new evidence supporting the systemic impacts of 0.1 sub-THz radiation, particularly on the immune system. It also enhanced the field of photoimmunology and offered valuable insights into the potential biomedical applications of 0.1 sub-THz radiation for treating autoimmune diseases.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The respiratory chain is a promising target for the development of new antimycobacterial agents, and a growing number of compounds have been reported and have entered clinical trials. We summarize ...the main features and the electron transfer process of the mycobacterial respiratory chain, and the recent progress in the search for new small molecule inhibitors targeting the respiratory chain of Mtb.
Display omitted
With the emergence of multidrug-resistant tuberculosis and extensive drug-resistant tuberculosis strains, there is an urgent need to develop novel drugs for the treatment of tuberculosis. The respiratory chain is a promising target for the development of new antimycobacterial agents, and a growing number of compounds have been reported and some have entered clinical trials. In this review, we summarize the main features and the electron transfer process of the mycobacterial respiratory chain, and the recent progress in the search for new small molecule inhibitors targeting the three main potential targets in the respiratory chain of Mycrobacterium tuberculosis. Our emphasis is on the optimization strategy of QcrB inhibitors and the challenges of developing QcrB inhibitors as antituberculosis drugs due to the alternate bd-type oxidase oxidative compensation pathway are discussed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
