- IMPROVED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
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The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2-isopropyl-4-methylpyridin-3-amine, useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.
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- IMPROVED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
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The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as 2,2',2"-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(3-fluorophenol), useful for the synthesis of compounds, such as Compound 9, for the treatment of KRAS G12C mutated cancers.
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- COMBINATION THERAPY INCLUDING A KRASG12C INHIBITOR AND ONE OR MORE ADDITIONAL PHARMACEUTICALLY ACTIVE AGENTS FOR THE TREATMENT OF CANCERS
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The present invention provides combination therapy that includes an KRASG12C inhibitor, such as (see Formula), or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.
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- IMPROVED SYNTHESIS OF KEY INTERMEDIATE OF KRAS G12C INHIBITOR COMPOUND
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The present invention relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound 5M, having the structure (I), useful for the synthesis of compounds that target KRAS G12C mutations, such as (II).
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- Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors
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KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
- Lanman, Brian A.,Allen, Jennifer R.,Allen, John G.,Amegadzie, Albert K.,Ashton, Kate S.,Booker, Shon K.,Chen, Jian Jeffrey,Chen, Ning,Frohn, Michael J.,Goodman, Guy,Kopecky, David J.,Liu, Longbin,Lopez, Patricia,Low, Jonathan D.,Ma, Vu,Minatti, Ana E.,Nguyen, Thomas T.,Nishimura, Nobuko,Pickrell, Alexander J.,Reed, Anthony B.,Shin, Youngsook,Siegmund, Aaron C.,Tamayo, Nuria A.,Tegley, Christopher M.,Walton, Mary C.,Wang, Hui-Ling,Wurz, Ryan P.,Xue, May,Yang, Kevin C.,Achanta, Pragathi,Bartberger, Michael D.,Canon, Jude,Hollis, L. Steven,McCarter, John D.,Mohr, Christopher,Rex, Karen,Saiki, Anne Y.,San Miguel, Tisha,Volak, Laurie P.,Wang, Kevin H.,Whittington, Douglas A.,Zech, Stephan G.,Lipford, J. Russell,Cee, Victor J.
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- KRAS G12C INHIBITORS AND METHODS OF USING THE SAME
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Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.
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