title: Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
abstract: A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA. Electronic address: xzheng@formatherapeutics.com.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Buckmelter
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Caligiuri
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Clodfelter
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Bingsong
authors.initials: B
authors.lastname: Han
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kley
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Chase C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.affiliation: Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C004711:dicyandiamido
keywords: Nampt; Nicotinamide phosphoribosyltransferase; X-ray crystal structure; cyanoguanidine