113237-20-0Relevant academic research and scientific papers
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.
, p. 52 - 65 (2020)
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).
RAS PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR THERAPEUTIC APPLICATIONS
-
Paragraph 0333, (2021/03/19)
Provided herein are RAS protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RAS-mediated disorder, disease, or condition.
Pyridopyrimidinone compound and application thereof
-
Paragraph 0182; 0185, (2021/01/24)
The invention provides a pyridopyrimidinone compound with a structure as shown in a general formula (II) and application thereof. Researches prove that the compound provided by the invention can effectively inhibit KRAS G12C mutation. KRAS mutation accounts for a large proportion in tumors, no approved drug is obtained for treatment at present, and the compound provided by the invention has the potential to become a therapeutic drug for malignant tumors (especially non-small cell lung cancer (NSCLC) and colorectal cancer) carrying KRAS G12C mutation, and has a great application value.
Kras-G12C inhibitor heterocyclic compounds
-
Paragraph 0038; 0043; 0262; 0278, (2021/03/31)
The invention relates to Kras-G12C inhibitor heterocyclic compounds and a preparation method thereof, and application of the compounds in prevention and treatment of tumor diseases such as lung cancer, colorectal cancer and pancreatic cancer. In the preparation process, the compounds provided by the invention are obtained through a series of reactions such as a condensation reaction, an intramolecular cyclization reaction, a chlorination reaction, an SN2 reaction, a coupling reaction, deprotection and the like.
IMPROVED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
-
Paragraph 0125; 0126, (2021/05/21)
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.
HETEROCYCLIC COMPOUNDS, PREPARATION METHODS AND USES THEREOF
-
Paragraph 0147-0148, (2021/06/26)
Disclosed herein are compounds, crystalline forms, and pharmaceutical compositions of Compound 1 and/or Compound 2. Also disclosed are methods of treating a disease or disorder such as a cancer or infectious disease that comprises administering to a subject in need thereof one or more of the compounds or compositions of the present disclosure.
COVALENT RAS INHIBITORS AND USES THEREOF
-
, (2021/06/04)
The disclosure features compounds, or pharmaceutically acceptable salts thereof, alone and in combination with other therapeutic agents, pharmaceutical compositions, and protein conjugates thereof, capable of modulating biological processes including Ras, and their uses in the treatment of cancers.
KRAS MUTANT PROTEIN INHIBITORS
-
, (2021/09/26)
KRAS mutant protein inhibitors of formula (I), a composition containing the inhibit-ors and the use thereof.
IMPROVED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
-
Paragraph 0127-0128; 0135-0137, (2021/05/21)
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.
KRAS inhibitor compound
-
Paragraph 0075-0079, (2020/07/24)
The invention provides a compound with a structure as shown in a formula II as described in the specification or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope marker thereof. The KRAS G12C inhibitor compound provided by the invention has a relatively good inhibition effect on KRAS mutation, and can be used for preventing and/or treating KRAS G12C mediated diseases.
