Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study

Zhong, Sheng; Zhang, Zhiyun; Guo, Zhen; Yang, Wenzhuo; Dou, Gaojing; Lv, Xiaye; Wang, Xinhui; Ge, Junliang; Wu, Bo; Pan, Xuefeng; Wang, Hongyu; Mou, Yonggao

doi:10.1080/21655979.2021.2011631

Cited by 22 publications

(9 citation statements)

References 54 publications

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“…The TNF-α antibody in iximab has been clinically proven to be effective in IBD patients (42,43). TNF-β triggers the activation of multiple signaling pathways, such as NF-κB and MAPK, which promote in ammatory response, cell survival, and angiogenesis (44). However, there is limited literature regarding the association of TNF-β with CD.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of Inflammatory bowel disease

liu,

Li,

Gao

et al. 2023

Preprint

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Objective The literature has previously reported the associations between inflammatory bowel disease (IBD) and certain inflammatory cytokines, such as CRP, IL-1, and TNFα. To additionally evaluate the causal relationships between 41 inflammatory cytokines and IBD, a Mendelian randomization (MR) study was conducted. Methods The two-sample MR investigation utilized data from three large publicly available genome-wide association studies (GWAS) on IBD, ulcerative colitis (UC), and Crohn's disease (CD) genetic variants. Additionally, inflammatory cytokine data from a GWAS meta-analysis, including 8,293 healthy individuals, were incorporated into the study. Causal relationships between exposures and outcomes were predominantly determined utilizing inverse variance-weighted methods. To evaluate the heterogeneity, pleiotropy, and stability of these genetic variants, the MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were conducted. Results The findings revealed that IL13 was linked to an elevated risk of IBD, UC, and CD, while MIF demonstrated a correlation with an elevated risk of CD. Conversely, TNF-related apoptosis-inducing ligand (TRAIL) was linked to a decreased risk of IBD and UC. Additionally, reverse MR analyses revealed that IBD was correlated with elevated levels of Monokine Induced by Gamma Interferon (MIG) and Stromal Cell-Derived Factor-1α (SDF1A), while UC showed an association with elevated levels of MIG and IL10. The CD was linked to elevated levels of stem cell factor (SCF) and decreased levels of TNF-β. Conclusion In the MR study, three upstream regulatory factors and five downstream regulatory factors were identified for IBD and its subtypes, providing avenues for developing new therapies for IBD.

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Section: Discussionmentioning

confidence: 99%

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of Inflammatory bowel disease

liu,

Li,

Gao

et al. 2023

Preprint

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“…To assess the safety of the adducts, the TOPKAT modules of Discovery Studio were selected to calculate the toxicity of the adducts and PhIP in this study. The original citations for data for this TOPKAT model were obtained from the USEPA AQUIRE database . A previous study showed that PhIP has direct-acting mutagenicity and that subchronic exposure to PhIP induces cancer risk; thus, the Ames mutagenicity and the lowest chronic oral observed adverse effect level (oral rat) in the TOPKAT model were chosen as the toxicity index parameters to compare the toxicity of the adducts against that of PhIP.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Inhibitory Effects of Selected Amino Acids on the Formation of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in both Benzaldehyde– and Phenylacetaldehyde–Creatinine Model Systems

Deng

Xue

et al. 2022

J. Agric. Food Chem.

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Although various inhibitors have been employed to react with phenylacetaldehyde to form adducts and thus interrupt the formation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), high concentrations of PhIP remain in the final system. It remains unknown whether other critical aldehyde or ketone intermediates are involved in the generation of PhIP, and scavenging these reactive carbonyls simultaneously may achieve higher inhibitory efficiency of PhIP. In this study, reactive carbonyls in a glucose/creatinine/phenylalanine model system were first identified by gas chromatography−mass spectrometry (GC−MS), and then the single and synergistic effects of nonprecursor amino acids (cysteine, methionine, proline, histidine, arginine, and leucine) on scavenging reactive carbonyls were investigated to find out promising combination partners. The obtained results showed that the concentrations of benzaldehyde and phenylacetaldehyde in the glucose/creatinine/phenylalanine model system reached 0.49 ± 0.01 and 6.22 ± 0.21 μg/mL, respectively. Heating these carbonyl compounds in the presence of creatinine resulted in the quantity of PhIP produced increasing linearly with the added quantity of benzaldehyde (r = 0.9733, P = 0.0002) and phenylacetaldehyde (r = 0.9746, P = 0.0002), indicating that both compounds are key intermediates for PhIP generation. Among the investigated amino acids, histidine produced the maximum inhibition of PhIP formation (78−99%) in the benzaldehyde/creatinine model system, and proline produced the maximum inhibition of PhIP formation (13−97%) in the phenylacetaldehyde/creatinine model system, where both compounds decreased PhIP formation in a dose-dependent manner. Histidine in combination with proline enhanced the inhibitory effect against PhIP formation at a low addition level, where the highest inhibitory efficiency was obtained using a 1:3 mass ratio of histidine to proline (2 mg/mL in total), reducing PhIP formation by 96%. These findings suggest that histidine−proline combinations can scavenge benzaldehyde and phenylacetaldehyde simultaneously, enhancing the suppression of PhIP formation.

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“…[5] There are several potential Akt inhibitors currently in phase II and phase III clinical trials including capivasertib, and ipatasertib. [5][6] The RalGEF pathway, on the other hand, has been relatively unexplored. There are no therapeutic agents targeting this pathway.…”

Section: Introductionmentioning

confidence: 99%

“…To date, there exists five FDA‐approved drugs that target the PI3K pathway, such as idelalisib and umbrakisib [5] . There are several potential Akt inhibitors currently in phase II and phase III clinical trials including capivasertib, and ipatasertib [5–6] . The RalGEF pathway, on the other hand, has been relatively unexplored.…”

Section: Introductionmentioning

confidence: 99%

Exploring Covalent Bond Formation at Tyr‐82 for Inhibition of Ral GTPase Activation

Landgraf,

Yeh,

Ghozayel

et al. 2023

ChemMedChem

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Ral RAS GTPases are directly activated by KRAS through a trimeric complex with a guanine exchange factor. Ral is considered undruggable and lacks an accessible cysteine for covalent drug development. Previously we had reported an aryl sulfonyl fluoride fragment that formed a covalent bond at Tyr‐82 on Ral and created a deep and well‐defined pocket. Here, we explore this pocket further through design and synthesis of several fragment derivatives. The fragment core is modified by introducing tetrahydronaphthalene or benzodioxane rings to enhance affinity and stability of the sulfonyl fluoride reactive group. The deep pocket in the Switch II region is also explored by modifying the aromatic ring of the fragment that is ensconced into the pocket. Compounds 19 (SOF‐658) and 26 (SOF‐648) formed a single robust adduct specifically at Tyr‐82, inhibited Ral GTPase exchange in buffer and in mammalian cells, and blocked invasion of pancreatic ductal adenocarcinoma cancer cells. Compound 19 (SOF‐658) was stable in buffer, mouse, and human microsomes suggesting that further optimization could lead to small molecules to probe Ral activity in tumor models.

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Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study

Cited by 22 publications

References 54 publications

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of Inflammatory bowel disease

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of Inflammatory bowel disease

Synergistic Inhibitory Effects of Selected Amino Acids on the Formation of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in both Benzaldehyde– and Phenylacetaldehyde–Creatinine Model Systems

Exploring Covalent Bond Formation at Tyr‐82 for Inhibition of Ral GTPase Activation

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