123639-56-5Relevant articles and documents
Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant gtpase krasg12c
Kettle, Jason G.,Bagal, Sharan K.,Bickerton, Sue,Bodnarchuk, Michael S.,Breed, Jason,Carbajo, Rodrigo J.,Cassar, Doyle J.,Chakraborty, Atanu,Cosulich, Sabina,Cumming, Iain,Davies, Michael,Eatherton, Andrew,Evans, Laura,Feron, Lyman,Fillery, Shaun,Gleave, Emma S.,Goldberg, Frederick W.,Harlfinger, Stephanie,Hanson, Lyndsey,Howard, Martin,Howells, Rachel,Jackson, Anne,Kemmitt, Paul,Kingston, Jennifer K.,Lamont, Scott,Lewis, Hilary J.,Li, Songlei,Liu, Libin,Ogg, Derek,Phillips, Christopher,Polanski, Radek,Robb, Graeme,Robinson, David,Ross, Sarah,Smith, James M.,Tonge, Michael,Whiteley, Rebecca,Yang, Junsheng,Zhang, Longfei,Zhao, Xiliang
, p. 4468 - 4483 (2020)
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.
TETRACYCLIC HETEROARYL COMPOUNDS
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Page/Page column 36; 41-42, (2020/01/10)
The specification relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
Formal Total Synthesis of (±)-Strictamine by [2,3]-Sigmatropic Stevens Rearrangements
Eckermann, Ruben,Breunig, Michael,Gaich, Tanja
supporting information, p. 3938 - 3949 (2017/03/27)
To date, more than 100 congeners of the akuammiline alkaloid family have been isolated. Their signature structural element is a methanoquinolizidine moiety, a cage-like scaffold structurally related to adamantane. The structural variations of the family members originate from oxidative processes that mostly trigger rearrangements of the methanoquinolizidine motif. The family of the akuammiline alkaloids is best represented by strictamine. It bears the least functionalized carbon skeleton of all family members without lacking the signature structural motifs. Herein, we report the formal synthesis of strictamine through a Stevens [2,3]-sigmatropic rearrangement as a key step and the synthetic pitfalls related with its synthesis.
