4/18/2023 0 Comments Quantum entanglerMore generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.read more read lessĪbstract: Saliency methods have emerged as a popular tool to highlight features in an input deemed relevant for the prediction of a learned model. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond. A key element in D-AMP is the use of an appropriate Onsager correction term in its iterations, which coerces the signal perturbation at each iteration to be very close to the white Gaussian noise that denoisers are typically designed to remove.read more read lessĪbstract: The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. We explain the exceptional performance of D-AMP by analyzing some of its theoretical features. We demonstrate that, when used with a high-performance denoiser for natural images, D-AMP offers the state-of-the-art CS recovery performance while operating tens of times faster than competing methods. This paper answers a natural question: How can one effectively employ a generic denoiser in a CS reconstruction algorithm? In response, we develop an extension of the approximate message passing (AMP) framework, called denoising-based AMP (D-AMP), that can integrate a wide class of denoisers within its iterations. Typical CS reconstruction algorithms can be cast as iteratively estimating a signal from a perturbed observation. A compressed sensing (CS) reconstruction algorithm seeks to recover a structured signal acquired using a small number of randomized measurements. Extensive research has been devoted to this arena over the last several decades, and as a result, todays denoisers can effectively remove large amounts of additive white Gaussian noise. Abstract: A denoising algorithm seeks to remove noise, errors, or perturbations from a signal.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |