Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

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.