Publications by authors named "R L Yauch"
Background: Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known.
Methods: A typical von Hippel-Lindau tumor suppressor (VHL)-PROTAC C-A947 (BRM degrader)-was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing.
Article Synopsis
- The study focuses on developing VHL-binding PROTACs that specifically target and degrade the BRM protein in lung cancer cells.
- These PROTACs show significant selectivity, degrading BRM up to 100 times more than its similar cousin, BRG1, and hinder the growth of BRG1-mutant NSCLC cells that rely on BRM.
- Further testing in animal models demonstrated that achieving over 95% BRM degradation is crucial for effective antitumor responses, linking BRM activity to tumor growth regulation.
Article Synopsis
- SMARCA2 and SMARCA4 are key proteins in a complex that helps manage DNA and gene activity, making SMARCA2 a promising target for cancer therapies, especially when SMARCA4 is mutated.
- Researchers developed a special rat model using CRISPR to safely study the effects of knocking out SMARCA2, avoiding issues related to younger animals.
- The study found no serious safety issues with SMARCA2 loss in mature rats, suggesting that targeting it in cancer treatments may be viable and safe for patients.
PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway.
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- Scientists studied a protein called SMARCA4 that often has mutations in cancer and found that cancer cells rely on another protein called SMARCA2 when SMARCA4 is broken.
- They created a special molecule called A947 that can specifically target and get rid of SMARCA2 without affecting other proteins.
- Tests showed that A947 works well against cancer cells with broken SMARCA4, offering hope for new treatments for patients with this kind of cancer.