Lumakras (sotorasib) / Amgen 
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  • ||||||||||  Lumakras (sotorasib) / Amgen
    Non-cationic macrocyclic peptides with on-target cellular inhibition of KRAS signaling (W183a (McCormick Place Convention Center)) -  Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_2381;    
    Recent breakthroughs with covalent small molecule inhibitors like sotorasib have rejuvenated efforts to drug mutant KRAS proteins...Concurrently, leveraging the NanoClick permeability assay, we identified targeted optimization of lipophilicity as a primary driver of cellular activity, enabling a transition to non-cationic permeable peptides with potent on-target activity in a variety of mutant-KRAS cancer cell lines but without any mast cell degranulation liability. These cell active peptides validate a unique inhibitory epitope on KRAS and provide valuable molecular templates for the development of novel therapeutics to address KRAS-driven cancers.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    PROTAC mediated degradation of KRAS (W183a (McCormick Place Convention Center)) -  Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_2380;    
    Rapid approval of Amgen’s mutant KRAS G12C inhibitor “Lumakras” by the FDA highlights the importance of KRAS dependent cancer, which was considered the most undruggable target in cancer therapy...KRAS PROTACs that employ novel ubiquitin ligases and degrade different KRAS mutant alleles will be the subject of this talk. The use of in-vitro ubiquitination to expedite novel PROTAC discovery, the choice of E3 ligase for certain targets and the relationship between ubiquitination (in vitro, in vivo) and PROTAC mediated degradation will be discussed.
  • ||||||||||  adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
    Identification of quinazoline-based covalent inhibitors of KRASG12C for the treatment of solid tumors (W183a (McCormick Place Convention Center)) -  Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_2376;    
    We optimized a novel series of mutant-selective KRASG12C quinazoline-based covalent inhibitors demonstrating high potency in a biochemical target engagement assay and pERK inhibition in NSCLC H358 cells. We will discuss SAR, parallel optimization of both potency and physicochemical properties, as well as in vivo efficacy and pharmacokinetic/pharmacodynamic markers assessment in tumor xenograft models.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    KRAS Inhibitor Profiling and SAR generation using a High Content Imaging Workflow (W186a (McCormick Place Convention Center)) -  Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_673;    
    Exciting progress with KRAS G12C inhibitors has been made with the first FDA approval of sotorasib in 2021 for treatment of NSCLC...This workflow converts high dimensional cell painting data into a scoring function of Euclidian distance (distance of a compounds phenotype from DMSO phenotype) and lysosomal score based on the phenotype of each compound. These scoring functions of high content imaging data are routinely used to rank compounds for selection of desired phenotypic effects to develop SAR.
  • ||||||||||  Lumakras (sotorasib) / Amgen
    Enrollment open:  Sotorasib in KRAS G12C Mutated, Resectable, Stage Ib-IIIA NSCLC (clinicaltrials.gov) -  Aug 2, 2022   
    P2,  N=25, Recruiting, 
    These scoring functions of high content imaging data are routinely used to rank compounds for selection of desired phenotypic effects to develop SAR. Not yet recruiting --> Recruiting
  • ||||||||||  Lumakras (sotorasib) / Amgen
    Trial completion date, Metastases:  AMG 510 Ethnic Sensitivity Study (CodeBreaK 105). (clinicaltrials.gov) -  Aug 1, 2022   
    P1,  N=12, Active, not recruiting, 
    Not yet recruiting --> Recruiting Trial completion date: Jul 2022 --> Mar 2023
  • ||||||||||  adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
    Journal:  The KRAS-G12C inhibitor: activity and resistance. (Pubmed Central) -  Jul 23, 2022   
    Unfortunately, the vast majority of patients do not respond to KRAS-G12C inhibitor therapy, mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors.