Figure
In Vitro Pharmacokinetic and Toxicology Profile of 18 and 19
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Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose pr...
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... in vitro pharmacokinetic profile of 18 reveals generally favorable properties with high solubility, low metabolism, and moderately high plasma protein binding (PPB), but low permeability with some evidence of efflux in the CaCo2 model (Table 5). This low permeability does not appear to impact either cellular activity or oral pharmacokinetics, where 18 shows good bioavailability in mice and rats despite moderately high clearance. ...Context 2
... expected from the high active site homology in the CaMK1 family, both 18 and 19 show limited selectivity between CaMK1A, CaMK1B, CaMK1D, and CaMK1G. More detailed secondary pharmacology screening with 18 and 19 reveals some evidence of hERG and CYP450 inhibition (Table 5) with the compounds demonstrating ∼300-fold selectivity over hERG based on cellular IC 50 . ...Citations
... The encoded protein is a component of the calcium-regulated calmodulin-dependent protein kinase cascade (Safran et al. 2021). CAMK1D has been suggested to play a role for liver gluconeogenesis, fat mass deposition, obesity and reduced insulin sensitivity (Rausch et al. 2018;Fromont et al. 2020). If fat deposition around the neck contributes to a more rounded/ arched neck shape in SWB horses, then the CAMK1D could be a candidate gene for this trait. ...
Swedish Warmblood horses (SWB) are bred for show jumping and/or dressage with young horse test scores as indicator traits. This study aimed to investigate possible candidate genes and regions of importance for evaluated and linearly scored young horse test traits. A single‐step genome‐wide association study (ssGWAS) was done using the BLUPF90 suite of programs for factors scores from factor analysis of traits assessed at young horse tests together with height at withers. The ssGWAS included 20,814 SWB with factors scores for four factors for evaluated traits. A total of 6436 of these horses also had factor scores for 13 factors for linearly scored traits. Genotypes from a 670K SNP array were available for 380 of the horses in this study. All genotyped horses had factor scores for evaluated traits, and 379 also had factors scores for linearly scored traits. Significant SNPs associated with three factors related to size were located on ECA3 within or nearby a well‐known region, including the genes ligand dependent nuclear receptor corepressor like ( LCORL ), non‐SMC condensin I complex subunit G ( NCAPG ), DDB1 and CUL4 Associated Factor 16 ( DCAF16 ), and the Family with Sequence Similarity 184 Member B ( FAM184B ). Significant SNPs were also detected for two factors for evaluated traits representing conformation and jumping, and four factors for linearly scored traits related to body length, neck conformation, walk and trot (hindleg position and activity), respectively. Among nearby genes, calcium/calmodulin‐dependent protein kinase type 1D ( CAMK1D ) for the factor for linearly scored traits related to neck conformation and GLI Family Zinc Finger 2 ( GLI2 ) for the factor for evaluated jumping traits, were most promising. For these, top associated SNPs were detected within the genes, and the known gene functions seems to be related to the phenotypes. In conclusion, ssGWAS is beneficial to detect plausible candidate genes/regions for desired traits in warmblood horses.
... The probes were further validated through pyrosequencing, which showed that the expression of the cg02323098 probe, named CAMK1D, was significantly downregulated compared with MG and control groups (P < 0.05). Related studies have found that CAMK1D is associated with lung adenocarcinoma cells, type 2 diabetes mellitus, and essential hypertension [25][26][27]. In addition, some studies have found that CAMK1D was a key regulator of tumor innate immune resistance [28]. ...
Myasthenia gravis (MG) is a common neuromuscular junction (NMJ) disorder and autoimmune disease mediated by several antibodies. Several studies have shown that genetic factors play an important role in MG pathogenesis. To gain insight into the epigenetic factors affecting MG, we report here genome-scale DNA methylation profiles of MG. DNA was extracted from 8 MG patients and 4 healthy controls for genome-wide DNA methylation analysis using the Illumina HumanMethylation 850K BeadChip. Verification of pyrosequencing was conducted based on differential methylation positions (DMPs). Subsequently, C2C12 and HT22 cell lines (derived from mouse) were treated with demethylation drugs. Transcribed mRNA of the screened differential genes were detected using quantitative Real-time PCR. The control and MG group were compared, and two key probe positions were selected. The corresponding genes were CAMK1D and CREB5 (P<0.05). Similarly, the myasthenic crisis (MC) and non-MC group were compared and four key probe positions were selected. The corresponding genes were SAV1, STK3, YAP1 and WWTR1 (P<0.05). Subsequently, pyrosequencing was performed for verification, revealing that hypomethylation of CAMK1D was significantly different between the MG and control group (P<0.001). Moreover, transcription of CREB5, PKD, YAP1 and STK3 genes in the C2C12 cells was downregulated (P<0.05) after drug treatment, but only YAP1 mRNA was downregulated in HT22 cells (P<0.05). This is the first study to investigate genome-scale DNA methylation profiles of MG using 850K BeadChip. The identified molecular markers of methylation may aid in the prevention, diagnosis, treatment and prognosis of MG.
... However, using a combination of homology modeling, machine learning and shape based virtual screening, we report a series of hit compounds with inhibitory low molecular binding potency toward PNCK. While other compounds have recently been reported to have activity against CAMK1b, they were part of a CAMK1D inhibitor campaign with non-selective activity against the family of CAM Kinases [37]. None of the compounds reported in this study, although commercially available, have any target annotation data and thus have not been previously characterized as kinase inhibitors. ...
PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.
... This both allows a CaMKK to access the activation loop, phosphorylating and activating it at T180, as well as allows substrates to access the active site [26]. Specific inhibitors have been developed for CaMK1D, intended for in vitro and in vivo studies on diabetes and triple-negative breast cancer, and these compounds were able to improve insulin sensitivity in diet-induced obese mice [28]. Here, two inhibitors were used: CS587, and CS640 ( Figure 2). ...
... Both of these are competitive inhibitors that engage in the ATP binding pocket and have IC50's for CaMK1D in the nanomolar range at both the enzymatic and cellular levels. Both also show a strong selectivity for CaMK1D over related kinases; however, due to highly conserved active sites within the CaMKI family, these compounds have limited selectivity for CaMK1D over other CaMKI isoforms [28]. Specific inhibitors have been developed for CaMK1D, intended for in vitro and in vivo studies on diabetes and triple-negative breast cancer, and these compounds were able to improve insulin sensitivity in diet-induced obese mice [28]. ...
... Both also show a strong selectivity for CaMK1D over related kinases; however, due to highly conserved active sites within the CaMKI family, these compounds have limited selectivity for CaMK1D over other CaMKI isoforms [28]. Specific inhibitors have been developed for CaMK1D, intended for in vitro and in vivo studies on diabetes and triple-negative breast cancer, and these compounds were able to improve insulin sensitivity in diet-induced obese mice [28]. Here, two inhibitors were used: CS587, and CS640 ( Figure 2). ...
Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.
... Overall, the risk allele of rs10830963 triggers a cascade of molecular changes facilitating diabetes. The rs11257655 risk allele shows allele-specific binding to FOXA1/FOXA2, thereby upregulating the transcription of CAMK1D, which increases gluconeogenesis and, therefore, the risk of diabetes (Figure 2) [104,105]. The risk allele of rs11257655 is associated with decreased methylation in the promoter region of CAMK1D, supporting the role of DNA methylation in the relationship between the risk allele, FOXA1/FOXA2 binding, and CAMK1D expression [84]. ...
Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.
Diabetes is a growing health concern, accompanied by significant complications like cardiovascular disease, kidney disease, and retinopathy. Metal ions, including iron, zinc, and copper, play a crucial role in maintaining human health through their balance within the body. Disruptions in metal ion balance can intensify diabetic conditions. For instance, iron overload induces oxidative stress, which harms islet β cells and impacts vascular complications of diabetes. Abnormal copper levels heighten insulin resistance, and zinc deficiency has a strong connection with type 1 diabetes. Future in - depth exploration of the association between metal metabolism and diabetes holds the potential to uncover novel treatment avenues, enhancing both the quality of life and health prognosis for patients.
Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications in drug discovery are underexplored, and efficient asymmetric synthetic methods are highly desirable. Here, we report a transition metal–free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen and high enantioselectivity. The reaction conditions were mild, and a wide range of enantioenriched aryl and alkyl sulfilimines were obtained. The synthetic utility and practicability of this robust protocol were further demonstrated through gram-scale reactions and late-stage functionalization of drugs.
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease worldwide. While injury to the podocytes, visceral epithelial cells that comprise the glomerular filtration barrier, drives albuminuria, proximal tubule (PT) dysfunction is the critical mediator of DKD progression. Here, we report that the podocyte-specific induction of human KLF6, a zinc-finger binding transcription factor, attenuates podocyte loss, PT dysfunction, and eventual interstitial fibrosis in a male murine model of DKD. Utilizing combination of snRNA-seq, snATAC-seq, and tandem mass spectrometry, we demonstrate that podocyte-specific KLF6 triggers the release of secretory ApoJ to activate calcium/calmodulin dependent protein kinase 1D (CaMK1D) signaling in neighboring PT cells. CaMK1D is enriched in the first segment of the PT, proximal to the podocytes, and is critical to attenuating mitochondrial fission and restoring mitochondrial function under diabetic conditions. Targeting podocyte-PT signaling by enhancing ApoJ-CaMK1D might be a key therapeutic strategy in attenuating the progression of DKD.
The Cecum is a key site for cellulose digestion in nutrient metabolism of intestine, but its mechanisms of microbial and gene interactions has not been fully elucidated during pathogenesis of obesity. Therefore, the cecum tissues of the New Zealand rabbits and their contents between the high-fat diet-induced group (Ob) and control group (Co) were collected and analyzed using multi-omics. The metagenomic analysis indicated that the relative abundances of Corallococcus_sp._CAG:1435 and Flavobacteriales bacterium species were significantly lower, while those of Akkermansia glycaniphila, Clostridium_sp._CAG:793, Mycoplasma_sp._CAG:776, Mycoplasma_sp._CAG:472, Clostridium_sp._CAG:609, Akkermansia_sp._KLE1605, Clostridium_sp._CAG:508, and Firmicutes_bacterium_CAG:460 species were significantly higher in the Ob as compared to those in Co. Transcriptomic sequencing results showed that the differentially upregulated genes were mainly enriched in pathways, including calcium signaling pathway, PI3K-Akt signaling pathway, and Wnt signaling pathway, while the differentially downregulated genes were mainly enriched in pathways of NF-kappaB signaling pathway and T cell receptor signaling pathway. The comparative analysis of metabolites showed that the glycine, serine, and threonine metabolism and cysteine and methionine metabolism were the important metabolic pathways between the two groups. The combined analysis showed that CAMK1, IGFBP6, and IGFBP4 genes were highly correlated with Clostridium_sp._CAG:793, and Akkermansia_glycaniphila species. Thus, the preliminary study elucidated the microbial and gene interactions in cecum of obese rabbit and provided a basis for further studies in intestinal intervention for human obesity.
