7196 research outputs found
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Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
No full textNimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114-substrate recognition, leading to inhibition of ubiquitination and degradation of tumor suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the use of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications
Tau deletion reduces beta-amyloid deposition by alleviating plaque-associated axonal damage
No full textAmyloid-β (Aβ) peptides, derived from the amyloid precursor protein, and the microtubule-associated protein tau are key pathogenic factors in Alzheimer’s disease. The prevalent ‘amyloid cascade hypothesis’ posits that Aβ aggregates trigger tau-related pathology. However, it remains controversial whether the connection between Aβ and tau is indeed unidirectional. We monitored the impact of tau deletion on the temporal progression of Aβ pathology by performing chronic in vivo two-photon microscopy in transgenic Alzheimer mice. Tau deletion did not postpone the onset of Aβ deposition but effectively ameliorated plaque-associated axonal pathology and slowed down Aβ deposition. Importantly, tau deletion alleviated the accumulation of BACE1 around plaques and interrupted the vicious pathogenic cycle of increased Aβ deposition. Hence, our results are potentially relevant to improve the efficacy of prospective BACE1 inhibition clinical trials
New guidelines for the pharmacokinetic and Drug drug interaction assessments of ADCS-input to templates for IQ consortium
No full textNovartis is member of IQ consortium on ADCs. Dominic Hainzl and myself represnet Novartis at Consortium to define new guidelines for Pharmacokinetic monitoring and DDI assessment of ADCs.
The final goal of consortium is to draft a white paper with cross comany recommendation. To accomplish this goal we need to populate the templates with preclinical and clinal information of ADcs. Although we have currently only 1 ADC program in clinical deveopment (PCA062) , we have not mentioned the Novartis code, nor the target. However, preclinical information about the payload (DM1) was shared at this information is already available. For other information provided information in these templates we have referred to public available information (journal articles) as listed below. We seek your approval to submit the prefilled templates to the IQ consortium.
papers from which we extracted information:
New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats. Walles M, Rudolph B, Wolf T, Bourgailh J, Suetterlin M, Moenius T, Peraus G, Heudi O, Elbast W, Lanshoeft C, Bilic S. Drug Metab Dispos. 2016 Jul;44(7):897-910. doi: 10.1124/dmd.115.069021. Epub 2016 Apr 27.
ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development.
Walles M, Connor A, Hainzl D. Curr Top Med Chem. 2017;17(32):3463-3475. doi: 10.2174/1568026618666180118153502. Review
Long-Acting Intraocular Delivery Strategies for Biological Therapy of Age-Related Macular Degeneration- A Review Article
No full textAge-related macular degeneration (AMD) is one of the leading causes of central vision loss in the elderly population. Treatment regimens for AMD, especially with biological agents, are complicated due to anatomical and physiological barriers, as well as administration of high doses and frequent regimens. Some clinical examples include monthly intravitreal administration of anti-VEGF antibody Lucentis® from Genentech and aflibercept (Eylea®) from Regeneron Pharmaceuticals. Long-acting sustained intraocular drug delivery provides promising solutions, such as Vitrasert® fromBausch & Lomb, an intravitreal implant made of a biodegradable polymer, poly (D,L-lactic co glycolic acid (PLGA), and can be used as a guiding reference to formulate sustained delivery systems. In this review, we discuss the anatomy and physiology of the eye, barriers to delivery, pathology of AMD, opportunities for biological therapeutics, and future prospects of intraocular delivery strategies that are in development for treatment of AMD
Evaluation of therapeutic effects of FAK inhibition in murine models of atherosclerosis
No full textObjective: Therapeutic effects of focal adhesion kinase (FAK) inhibition using a small molecule inhibitor was evaluated in apolipoprotein E (apoE) knockout (KO) and low-density lipoprotein receptor (LDLr) KO mouse atherosclerosis models.
Results: The prevention trial consisted of 8-week concurrent treatment with a high fat (HF) / high cholesterol (HC) diet. The intervention trial consisted of 6- and 8-week treatment after 6- and 8-week pre-loading of a HF/HC diet in apoE KO and LDLr KO mice, respectively. The inhibitor was admixed with a HF/HC diet and mice were given free access to the admixture. The FAK inhibitor exhibited marked inhibition against the development of the atherosclerosis in both of prevention and intervention trials at a dose of 0.03% without showing any remarkable toxic properties in biochemical examinations. These results indicated that FAK inhibition might be a possible candidate for novel therapeutic targets against atherosclerosis
PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer
No full textThe combination of CDK4/6 inhibitors with anti-estrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Since PTEN loss also causes resistance to PI3Kalpha-inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment sequencing strategies
Elevated oxysterol levels in human and mouse livers reflect non-alcoholic steatohepatitis
No full textNon-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7α,25-diHC-system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared to controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype related differences were observed in Ebi2-/- animals and animals with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by enhanced level of 7α-hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH
α-Klotho regulates age-associated vascular mineralization and lifespan in zebrafish
No full textα-Klotho is an anti-aging hormone regulating mineral homeostasis together with Fibroblast Growth Factor-23 (FGF23) in mammals. Cellular and molecular mechanisms through which these signals regulate age-related conditions, such as vascular mineralization remain intriguing. It is not known if aging mechanisms controlled by α-Klotho/FGF23 signaling are evolutionarily conserved. To this end, we generated knockouts carrying homozygous mutations in α-klotho and fgf23 in zebrafish. Both knockouts display an adult-onset decline in body condition and behavior, and an early-onset morbidity. Bulbus arteriosus, the outflow tract of zebrafish heart shows extensive mineralization in the mutants. RNA-seq analysis of kidney, heart and gills shows an ectopic activation of bone-remodeling pathway, extracellular matrix remodeling factors osteoclast differentiation and inflammation in the vasculature. Taken together, these findings indicate a conserved role of α-Klotho/FGF23 signaling in regulating vertebrate life span and identify molecular mechanisms underlying vascular mineralization
The comparison of the performance of 3 T and 7 T T mapping for untreated low-grade cartilage lesions.
No full textOBJECTIVE:
To investigate T mapping as a possible marker for low-grade human articular cartilage lesions during a one-year follow-up, possible changes during the follow-up and compare the reliability and sensitivity of these measurements on high-field (3 T) and ultra-high-field (7 T) MRI scanners.
DESIGN:
Twenty-one patients with femoral, tibial and patellar cartilage defect in the knee joint participated in the study. The MRI protocol consisted of morphological, as well as three-dimensional triple-echo steady-state (3D-TESS) T2 mapping sequences with similar parameters at 3T and 7T. Patients were scanned at five time-points up to 12 months. T2 values were evaluated in the lesion and healthy-appearing regions for superficial and deep cartilage zone. The repeated ANOVA was used to determine differences in T2 values at various time points.
RESULTS:
A significant decrease in T2 values was observed between baseline and six months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 ± 9.3 ms to 31.21 ± 7.2 ms, which is a difference of -5.67 ± 2.2 ms (p = 0.031)), and at 12 months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 ± 9.3 ms to 35.28 ± 4.9 ms, which is a difference of -6.60 ± 4.4 ms (p = 0.044). No significant differences were recorded at 7 T.
CONCLUSION:
The change in T2 values acquired with 3 T 3D-TESS appears to be reflecting subtle changes of cartilage composition in the course of low-grade lesion development. 7 T T2 mapping does not reflect these changes probably due to completely decayed short T2 component
Finding synergies for the 3Rs – Repeated Dose Toxicity testing: Report from an EPAA Partners' Forum
No full textThe European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the use of chemicals. Currently there are no validated alternatives to repeated dose testing and a direct one-to-one replacement is not appropriate. However, there are many projects and initiatives at the international level which aim to implement various aspects of replacement, reduction and refinement (the 3Rs) in RDT testing. Improved definition of use, through better problem formulation, aligned to harmonisation of regulations is a key area, as is the more rapid implementation of alternatives into the legislative framework. Existing test designs can be optimised to reduce animal use and increase information content. Greater use of exposure-led decisions and improvements in dose selection will be beneficial. In addition, EPAA facilitates sharing of case studies demonstrating the use of Next Generation Risk Assessment applying various New Approach Methodologies to assess RDT