Showing papers by "Michel A. Duchosal published in 2022"
TL;DR: It is demonstrated that the NAPRT inhibitor 2-hydroxynicotinic acid (2-HNA) cooperates with the NAMPT inhibitor FK866 in killing NAP RT-proficient cancer cells that were otherwise insensitive to FK850 alone.
Abstract: Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been conceived as a promising anti-cancer strategy. Numerous inhibitors of the NAD-producing enzyme, nicotinamide phosphoribosyltransferase (NAMPT), have been developed over the past two decades. However, their limited anti-cancer activity in clinical trials raised the possibility that cancer cells may also exploit alternative NAD-producing enzymes. Recent studies show the relevance of nicotinic acid phosphoribosyltransferase (NAPRT), the rate-limiting enzyme of the Preiss–Handler NAD-production pathway for a large group of human cancers. We demonstrated that the NAPRT inhibitor 2-hydroxynicotinic acid (2-HNA) cooperates with the NAMPT inhibitor FK866 in killing NAPRT-proficient cancer cells that were otherwise insensitive to FK866 alone. Despite this emerging relevance of NAPRT as a potential target in cancer therapy, very few NAPRT inhibitors exist. Starting from a high-throughput virtual screening approach, we were able to identify and annotate two additional chemical scaffolds that function as NAPRT inhibitors. These compounds show comparable anti-cancer activity to 2-HNA and improved predicted aqueous solubility, in addition to demonstrating favorable drug-like profiles.
6 citations
TL;DR: More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK-866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1-4-dimethyl and 2- and 3-carbon tethers as discussed by the authors .
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.
3 citations
TL;DR: In this article , the effect of the interaction between microbiota and cancer cells was explored in a tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866.
Abstract: Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD+) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet.
3 citations
TL;DR: It is identified that cancer patient experiences can be improved in relation to communication, information and supportive care aspects and improvement efforts should target these areas of care to enhance responsiveness of cancer care.
Abstract: Abstract Objectives The objectives were to describe patients' experiences of cancer care in Switzerland and explore the variation of these experiences by type of cancer. Methods The Swiss Cancer Patient Experiences (SCAPE) study was a cross‐sectional, multicentre survey conducted in 2018. Adult patients (n = 7145) with breast, prostate, lung, colorectal, skin or haematological cancer from four large hospitals in French‐speaking Switzerland were invited to complete a survey. Logistic regressions were used to assess whether experiences varied according to cancer type, adjusting for confounders. Results Of the 3121 persons who returned the survey (44% response rate), 2755 reporting an eligible cancer were included in the analyses. Participants' average score for overall care was 8.5 out of a maximum score of 10. Higher rates of positive experiences were found for nurse consultations (94%), diagnostic tests (85%) and inpatient care (82%). Lower positive responses were reported for support for people with cancer (70%), treatment decisions (66%), diagnosis (65%) and home care (55%). We observed non‐systematic differences in experiences of care by cancer type. Conclusions This large study identified that cancer patient experiences can be improved in relation to communication, information and supportive care aspects. Improvement efforts should target these areas of care to enhance responsiveness of cancer care.
3 citations
TL;DR: In this article , the authors presented characteristics and outcomes in a cohort of patients with T-PLL undergoing auto-HCT, and the 2-year OS was estimated at 44% (95% CI, 28-59%).
TL;DR: It is demonstrated that NAPRT is amplified and overexpressed in several types of solid tumors and that its expression is a critical determinant of cancer cell susceptibility to NAMPT inhibitors, and in silico molecular docking screens are a promising approach to identify new NAP RT inhibitors with anticancer effects.
Abstract:
Cancer cells rely heavily on sustained NAD levels to support their survival and proliferation. Thus, depleting NAD levels in tumor cells through interference with their NAD-biosynthetic machinery has been proposed as a promising anticancer strategy. Several pathways contribute to NAD production in mammals, such as the de novo and the Preiss-Handler (PH) pathways, which generate NAD from tryptophan and from nicotinic acid, respectively. In addition, the NAD salvage pathway, which utilizes nicotinamide as a substrate, is also a major NAD-producing route and its rate-limiting enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is commonly overexpressed in a multitude of human cancers. Over the past two decades, several potent NAMPT inhibitors have been developed, such as FK866. However, their clinical efficacy has proven limited, suggesting that the other NAD-producing routes are frequently also active in cancer cells and are responsible for causing resistance to NAMPT inhibitors. Recently, we have shown nicotinic acid phosphoribosyl transferase (NAPRT), the key enzyme in the PH pathway, to play an important role in NAD metabolism in cancer cells. We demonstrated that NAPRT is amplified and overexpressed in several types of solid tumors and that its expression is a critical determinant of cancer cell susceptibility to NAMPT inhibitors. Although several NAPRT inhibitors have been reported, including 2-hydroxy nicotinic acid (2-HNA), their low potency and/or poor solubility limit their clinical applicability. To identify new NAPRT inhibitors with enhanced pharmacological profiles, we performed a high-throughput molecular docking screen, taking advantage of the availability of NAPRT crystal structure. The first 500 hits were visually inspected to prioritize compounds that reproduced, at least in part, the putative binding mode of known substrates and inhibitors and complied with simple physicochemical rules such as Lipinski’s rule of five. In addition, several 2-HNA analogs were selected. Altogether, this led to a final list of 50 compounds that were tested in vitro. We show that four compounds from this list were able to sensitize NAPRT-overexpressing ovarian cancer cells to FK866, resulting in a more significant reduction in intracellular NAD levels, as well as in a much more pronounced cytotoxicity as compared to FK866 alone. The inhibitory constant (Ki) of the new NAPRT inhibitors was found to be in the micromolar range. In conclusion, in silico molecular docking screens are a promising approach to identify new NAPRT inhibitors with anticancer effects.
Citation Format: Moustafa Ghanem, Amr Khalifa, Irene Caffa, Aimable Nahimana, Michel Duchosal, Alberto Del Rio, Santina Bruzzone, Francesco Piancente, Alessio Nencioni. Identification of nicotinic acid phosphoribosyltransferase inhibitors with anticancer properties by in silico drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6254.