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Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

Journal Article · · PLoS ONE
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  1. Genentech, Inc., South San Francisco, CA (United States)
  2. Forma Therapeutics, Inc., Watertown, MA (United States)
  3. Univ. of Washington, Seattle, WA (United States)
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Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an α-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH)
OSTI ID:
1255305
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 10 Vol. 9; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Dependence of Tumor Cell Lines and Patient-Derived Tumors on the NAD Salvage Pathway Renders Them Sensitive to NAMPT Inhibition with GNE-618 journal October 2013
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Cited By (6)

New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology journal June 2015
Cross resistance to diverse anticancer nicotinamide phosphoribosyltransferase inhibitors induced by FK866 treatment journal March 2018
Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells text January 2017
Nicotinamide phosphoribosyltransferase (Nampt) in carcinogenesis: new clinical opportunities journal June 2016
Extracellular nicotinamide phosphoribosyltransferase, a new cancer metabokine journal June 2016
Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA journal March 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Crystal structure
Enzyme inhibitors
Enzyme structure
Enzymes
Imidazole
Mutation detection
Nicotine
Protein structure