Lumakras (sotorasib) / Amgen 
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  • ||||||||||  Lumakras (sotorasib) / Amgen
    Journal:  Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations. (Pubmed Central) -  Oct 20, 2022   
    To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green.While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib's binding to KRAS. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral pharmaceutical agents.
  • ||||||||||  Tagrisso (osimertinib) / AstraZeneca, Lumakras (sotorasib) / Amgen
    Journal, Tumor-specific neoantigens:  Creating MHC-restricted neoantigens with covalent inhibitors that can be targeted by immune therapy. (Pubmed Central) -  Oct 18, 2022   
    Notably, it is effective against KRASG12C mutant cells with different HLA supertypes, HLA-A*02 and A*03/11, suggesting loosening of MHC restriction. Our strategy creates targetable neoantigens by design, unifying targeted and immune therapies.
  • ||||||||||  Tabrecta (capmatinib) / Incyte, Novartis, Lumakras (sotorasib) / Amgen
    Molecular landscape of Indian NSCLC: Is NGS the answer? (Exhibition / Poster Area) -  Oct 9, 2022 - Abstract #ESMOAsia2022ESMO_Asia_887;    
    Our results support the implementation of diagnostic NGS in NSCLC to allow patients access to the most appropriate molecularly targeted therapy. In addition, we also advocate performing panel based upfront NGS testing in patients with squamous histology as well, especially in the light of recent approvals of capmatinib and sotorasib fro MET exon 14 skipping and KRAS G12C alterations.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    Let’s bring back old drugs to conquer resistance to KRAS G12C inhibitors in NSCLC (Exhibition / Poster Area) -  Oct 9, 2022 - Abstract #ESMOAsia2022ESMO_Asia_814;    
    In KRAS-mutant lung adenocarcinomas that have received previous anticancer therapies, treatment with a selective KRAS G12C inhibitor (sotorasib) causes partial responses in around 38 % of patients...Two of the drugs have shown considerably good cytotoxicity against A549 cells. Conclusions Cotreatment of cells with a SHP2 inhibitor, resulted in more persistent ERK suppression by preventing RTK-mediated MAPK pathway reactivation.
  • ||||||||||  adagrasib (MRTX849) / Mirati, ARS-1620 / Kura Oncology, J&J, Araxes Pharma, Lumakras (sotorasib) / Amgen
    Journal:  Fluorescent Biosensor for Measuring Ras Activity in Living Cells. (Pubmed Central) -  Sep 30, 2022   
    We found in living cells a residual Ras activity lingers for hours in the presence of these inhibitors. Together, RasAR represents a powerful molecular tool to enable live-cell interrogation of Ras activity and facilitate the development of Ras inhibitors.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    Journal:  Modeling receptor flexibility in the structure-based design of KRAS inhibitors. (Pubmed Central) -  Sep 29, 2022   
    In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRAS, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors...Using this methodology, the mean unsigned error (MUE) of binding affinity prediction were reduced from 1.44 to 0.89 kcal/mol on a set of 14 compounds. These approaches were of significant use in facilitating the structure-based design of KRAS inhibitors and are anticipated to be of further use in the design of covalent (and noncovalent) inhibitors of other conformationally labile protein targets.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    Preclinical, Journal:  Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers. (Pubmed Central) -  Sep 20, 2022   
    All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts...Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h-bonds, and potent inhibition against G13D K-Ras. As a result, the current research identifies prospective K-Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K-Ras-driven cancers.