title: Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities.
abstract: Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) has the potential to directly limit NAD production in cancer cells and is an effective strategy for cancer treatment. Using a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of NAMPT. Several designed compounds showed promising antiproliferative activities in vitro. (E)-N-(5-((4-(((2-(1H-Indol-3-yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3-yl)acrylamide, 30, bearing an indole moiety, has an IC50 of 25.3 nM for binding to the NAMPT protein and demonstrated promising inhibitory activities in the nanomolar range against several cancer cell lines (MCF-7 GI50 = 0.13 nM; MDA-MB-231 GI50 = 0.15 nM). Triple-negative breast cancer is the most malignant subtype of breast cancer with no effective targeted treatments currently available. Significant antitumor efficacy of compound 30 was achieved (TGI was 73.8%) in an orthotopic MDA-MB-231 triple-negative breast cancer xenograft tumor model. This paper reports promising lead molecules for the inhibition of NAMPT which could serve as a basis for further investigation.
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Bai
authors.affiliation: School of Medical Engineering, Hefei University of Technology , Hefei, Anhui 230009, China.
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Yanghan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Yatao
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.|ABA Chemicals Corporation , Shanghai 200063, China.
authors.forename: Dongguang
authors.initials: D
authors.lastname: Qin
authors.affiliation: The Houston Methodist Research Institute , Houston, Texas 77030, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Zheng-Chao
authors.initials: ZC
authors.lastname: Tu
authors.affiliation: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences , 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human