Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50 = 0.93 ± 0.29 nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents.
Highlights
CHS-828 and FK866, have been progressed to clinical trials
We carried out a high throughput screening (HTS) using recombinant human Nicotinamide phosphoribosyltransferase (NAMPT) (Fig. S1) on a chemical library containing 24434 small-molecules at 20 μ M
To guarantee the quality of screening, S/N ratio, Coefficients of variation (CV) and Z’ factors were monitored throughout the screenings, and all three indices met the requirements of HTS (Fig. S2)
Summary
CHS-828 and FK866, have been progressed to clinical trials. CHS-828 is in phase I clinical trials[12], and FK866 is in phase II clinical trials[13,14]. CHS-828 exhibits large pharmacokinetic variation, thrombocytopenia and gastrointestinal toxicity[14]. FK866 exhibits low bioavailability, rapid intravenous clearance and thrombocytopenia[13]. It is highly desirable to discover novel NAMPT inhibitors as probes or lead compounds to investigate the biological function of NAMPT and development of antitumor drug candidates. We identified a potent NAMPT inhibitor MS0 from our HTS platform and obtained novel structural analogues with high potency. The new inhibitors were used as chemical probes to clarify structure activity relationship, target engagement in living cells as well as the molecular action mode
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