title: Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer.
abstract: The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(50): 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1.
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, United States.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Seong A
authors.initials: SA
authors.lastname: Kang
authors.forename: Carson C
authors.initials: CC
authors.lastname: Thoreen
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Tausif
authors.initials: T
authors.lastname: Ahmed
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004355:Drug Stability; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D000631:Aminopyridines; D000970:Antineoplastic Agents; D009287:Naphthyridines; D058570:TOR Serine-Threonine Kinases