title: Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
abstract: Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472, USA. xzheng@formatherapeutics.com
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Paul
authors.initials: P
authors.lastname: Bauer
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Maureen
authors.initials: M
authors.lastname: Caligiuri
authors.forename: Karl H
authors.initials: KH
authors.lastname: Clodfelter
authors.forename: Bingsong
authors.initials: B
authors.lastname: Han
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kley
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.forename: Chase C
authors.initials: CC
authors.lastname: Smith
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014508:Urea; D054409:Nicotinamide Phosphoribosyltransferase