title: Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
abstract: The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dragovich.peter@gene.com.
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: Guiling
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bravo
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.affiliation: Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Rongbao
authors.initials: R
authors.lastname: Hua
authors.affiliation: Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Guangkun
authors.initials: G
authors.lastname: Li
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
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: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.affiliation: Crown Bioscience, Science & Technology Innovation Park, No.6 Beijing West Road, Taicang City, Jiangsu Province, PR China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.affiliation: Crown Bioscience, Science & Technology Innovation Park, No.6 Beijing West Road, Taicang City, Jiangsu Province, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000631:Aminopyridines; D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; C031283:3-aminopyridine; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Fragment-based design; NAMPT; Nicotinamide phosphoribosyltransferase; Structure-based design; Surface plasmon resonance; X-ray crystal structure