Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

Abstract

Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

“…S1A) that inhibits the biochemical activity of NAMPT with an IC 50 of 5 nmol/L and exhibits efficacy in xenograft models of cancer (26). As expected, this molecule causes rapid depletion of cellular NAD followed by a decrease in ATP (Supplementary Fig.…”

Depletion of the Central Metabolite NAD Leads to Oncosis-mediated Cell Death

“…Chemicals and Reagents-GNE-617 was synthesized inhouse at Genentech (6). All other reagents used in this study were purchased from the following sources: VX680 (T-2304; LC Laboratories), taxol (1097; Tocris Bioscience), trichostatin A (T8552; Sigma), ouabain (03125; Sigma), propidium iodide (P4864; Sigma), staurosporin (569396; Calbiochem), temozolomide (420-044; Enzo), Oliparib (O-9201; LC Laboratories), Fluo-4-AM (F-1420; Invitrogen), and CyQUANT Direct Cell Proliferation Assay (Invitrogen).…”

“…Small molecule inhibitors directed against NAMPT have been described and shown to deplete NAD in cancer cells and induce cell death (2)(3)(4)(5)(6), thus emphasizing the importance of NAD in cancer cell survival.…”

“…Some examples include apoptosis (loss of mitochondrial potential and cell blebbing), autophagy (cytoplasmic vacuolization), and oncosis (cellular swelling and rapid decrease in ATP), all of which can culminate in necrosis, which is characterized by the appearance of disrupted nuclei and membranes. Given the diverse roles and functions for NAD, it is not surprising that depletion of NAD results in cell death (2)(3)(4)(5)(6). Although there are reports that inhibition of NAMPT can increase cellular ROS levels (19) and promote apoptosis (19,20), it has also been reported that NAMPT inhibition can induce autophagy (21,22).…”

Understanding Tumour Metabolic Reprogramming with Metabolomics

“…Since then, several companies are now pursuing this target and many publications have been produced (Gunzner-Toste et al, 2013;Tan et al, 2013;Zheng et al, 2013), but one recent work by Cagnetta et al (2013) provides a striking example of how metabolic targets may be successfully combined with a targeted therapy to enhance activity and overcome resistance. The proteosome inhibitor bortezomib has generated strong responses in multiple myeloma but faces limitations due to dose-limiting toxicities and the development of resistance.…”