3682-31-3Relevant articles and documents
Structural identification between phthalazine-1,4-diones and n-aminophthalimides via vilsmeier reaction: Nitrogen cyclization and tautomerization study
Chung, Cheng-Yen,Tseng, Ching-Chun,Li, Sin-Min,Tsai, Shuo-En,Lin, Hui-Yi,Wong, Fung Fuh
supporting information, (2021/05/31)
N-aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3dione with monohydrate hydrazine to carry out the 5-exo or 6-endo nitrogen cyclization under the different reaction conditions. Based on the control experimental results, 6-endo thermodynamic hydrohydrazination and kinetical 5-exo cyclization reactions were individually selective formation. Subsequently, Vilsmeier amidination derivatization was successfully developed to probe the structural divergence between N-aminophthalimide 2 and phthalazine 1,4-dione 3. On the other hand, the best tautomerization of N-aminophthalimide to diazinone was also determined under acetic acid mediated solution.
Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors
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.
supporting information, p. 52 - 65 (2020/01/09)
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).
KRAS G12C INHIBITORS AND METHODS OF USING THE SAME
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, (2018/07/15)
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.
