Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).
Hengmiao ChengSuvi T M OrrSimon BaileyAlexei BroounPing ChenJudith G DealYali L DengMartin P EdwardsGary M GallegoNeil GrodskyBuwen HuangMehran JalaieStephen KaiserRobert S KaniaSusan E KephartJennifer LafontaineMartha A OrnelasMason PairishSimon P PlankenHong ShenScott SuttonLuke ZehnderChau D AlmadenShubha BagrodiaMatthew D FalkHovhannes J GukasyanCaroline HoXiaolin KangRachel E KosaLing LiuMary E SpilkerSergei TimofeevskiRavi VisswanathanZhenxiong WangFanxiu MengShijian RenLi ShaoFeng XuJohn C KathPublished in: Journal of medicinal chemistry (2020)
The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.
Keyphrases
- endothelial cells
- papillary thyroid
- signaling pathway
- induced pluripotent stem cells
- squamous cell
- newly diagnosed
- end stage renal disease
- cell proliferation
- small molecule
- quality improvement
- pluripotent stem cells
- epithelial mesenchymal transition
- prognostic factors
- lymph node metastasis
- adverse drug
- childhood cancer
- tyrosine kinase
- protein kinase
- induced apoptosis