2158303-49-0Relevant academic research and scientific papers
Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with in Vivo Activity
Fell, Jay B.,Fischer, John P.,Baer, Brian R.,Ballard, Joshua,Blake, James F.,Bouhana, Karyn,Brandhuber, Barbara J.,Briere, David M.,Burgess, Laurence E.,Burkard, Michael R.,Chiang, Harrah,Chicarelli, Mark J.,Davidson, Kevin,Gaudino, John J.,Hallin, Jill,Hanson, Lauren,Hee, Kenneth,Hicken, Erik J.,Hinklin, Ronald J.,Marx, Matthew A.,Mejia, Macedonio J.,Olson, Peter,Savechenkov, Pavel,Sudhakar, Niranjan,Tang, Tony P.,Vigers, Guy P.,Zecca, Henry,Christensen, James G.
, p. 1230 - 1234 (2018)
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.
A COMPOUND HAVING INHIBITORY ACTIVITY AGAINST KRAS G12D MUTATION
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Paragraph 0300-0301, (2021/06/04)
The present invention relates to a compound having inhibitory activity against KRAS G12D mutation or a salt thereof, and relates to a pharmaceutical composition comprising the compound as an active ingredient.
PYRAZOLE-CONTAINING MACROPHAGE MIGRATION INHIBITORY FACTOR INHIBITORS
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Page/Page column 108; 109, (2019/10/04)
In one aspect, the invention comprises compounds that bind and inhibit macrophage migration inhibitory factor. In another aspect, the invention provides methods of treating inflammatory disease, neurological disorders and cancer using the compounds of the invention.
MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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Paragraph 001230-001231, (2019/10/29)
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor
Trivedi-Parmar, Vinay,Robertson, Michael J.,Cisneros, José A.,Krimmer, Stefan G.,Jorgensen, William L.
supporting information, p. 1092 - 1097 (2018/04/30)
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto–enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60–70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl–aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.
