Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/anie.202109237 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Geographic risk assessment of Batrachochytrium salamandrivorans invasion in Costa Rica as a means of informing emergence management and mitigation.
PLoS One
December 2024
Warnell School of Forestry, University of Georgia Athens, Athens, Georgia, United States of America.
Remotely-sensed risk assessments of emerging, invasive pathogens are key to targeted surveillance and outbreak responses. The recent emergence and spread of the fungal pathogen, Batrachochytrium salamandrivorans (Bsal), in Europe has negatively impacted multiple salamander species. Scholars and practitioners are increasingly concerned about the potential consequences of this lethal pathogen in the Americas, where salamander biodiversity is higher than anywhere else in the world.
View Article and Find Full Text PDFMOUNTAINEER-03 phase III study design: first-line mFOLFOX6 + tucatinib + trastuzumab for HER2+ metastatic colorectal cancer.
Future Oncol
December 2024
Department of Medical Oncology, Sorbonne Université et Hôpital Saint Antoine, Paris, France.
Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2-3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3-4% in mCRC and increases up to 8% in patients with // wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), WT mCRC in the MOUNTAINEER trial.
View Article and Find Full Text PDFRecurring incursions and dissemination of novel Eurasian-origin H5Nx avian influenza viruses in Atlantic Canada.
Virus Evol
December 2024
Department of Biology, Memorial University of Newfoundland, St. John's, NL A1C 5S7, Canada.
Wild birds are important hosts of influenza A viruses (IAVs) and play an important role in their ecology. The emergence of the A/goose/Guangdong/1/1996 H5N1 (Gs/GD) lineage marked a shift in IAV ecology, leading to recurrent outbreaks and mortality in wild birds from 2002 onwards. This lineage has evolved and diversified over time, with a recent important derivative being the 2.
View Article and Find Full Text PDFNeural network-based dynamic target enclosing control for uncertain nonlinear multi-agent systems over signed networks.
Neural Netw
December 2024
School of Aeronautics and Astronautics, University of Electronic Science and Technology of China, Chengdu, 611731, Sichuan, China; Aircraft Swarm Intelligent Sensing and Cooperative Control Key Laboratory of Sichuan Province, Chengdu, 611731, Sichuan, China. Electronic address:
Neural networks have significant advantages in the estimation of uncertainty dynamics, which can afford highly accurate prediction outcomes and enhance control robustness. With this in mind, this study presents a neural network-based method to investigate the uncertain target enclosing control problem for multi-agent systems over signed networks. Firstly, a nominal target enclosing controller is constructed by adding the target information component into the classical bipartite consensus error, in which the multi-agent system can be grouped to enclose the target from opposite sides.
View Article and Find Full Text PDFCaBP1 and 2 enable sustained Ca1.3 calcium currents and synaptic transmission in inner hair cells.
Elife
December 2024
Experimental Otology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.
To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their Ca1.3 calcium channels. Mutations in the gene underlie non-syndromic autosomal recessive hearing loss DFNB93.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!