Dec 29, 2020 · KRAS G12C Inhibitors . Sotorasib . Activity focused on KRAS G12C took off recently following the discovery of a shallow switch II pocket in the mutant KRAS G12C protein, which enabled the development of covalent inhibitors of KRAS G12C. 1,4. Sotorasib (AMG 510) was one of the first such molecules to enter human clinical trials.
With the discovery of a unique surface groove in the KRAS G12C protein, Amgen developed and advanced the first investigational KRAS G12C inhibitor into the clinic and is exploring the potential of KRAS G12C inhibition across multiple tumor types for patients who remain in dire need of treatment options. 1, 10
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Sotorasib (formerly AMG 510) targets a specific mutation, known as KRAS G12C, found in about 14% of non-small-cell lung cancer (NSCLC) and a smaller proportion of other solid tumors. In the Phase I/II CodeBreaK 100 study, sotorasib led to tumor shrinkage in 32% of patients with advanced NSCLC.
Nov 07, 2012 · However, in tumors and normal cells with wild-type RAF, these inhibitors stimulate ERK signaling in a RAS-dependent manner. 8,12-16 This paradoxical activation is thought to explain why this class ...
Direct factor Xa inhibitors ('xabans') are a class of anticoagulant drugs which act directly upon factor X in the coagulation cascade, without using antithrombin as a mediator.  Antistasin , the first discovered naturally occurring direct Xa inhibitor
Two features of KRAS confound its tractability as a drug target: (1) KRAS binds to GDP and GTP with picomolar affinity, severely hindering efforts to develop nucleotide-competitive inhibitors, and (2) the KRAS protein lacks other deep surface hydrophobic pockets, thwarting efforts to identify high-affinity allosteric inhibitors.