Nicotinamide Phosphoribosyltransferase Inhibitor as a Novel Payload for Antibody–Drug Conjugates

Karpov, Alexei S.; Abrams, Tinya J.; Clark, Suzanna; Raikar, Ankita; D’Alessio, Joseph A.; Dillon, Michael P.; Gesner, Thomas G.; Jones, Darryl; Lacaud, Marion; Mallet, William; Martyniuk, Piotr; Meredith, Erik; Mohseni, Morvarid; Nieto‐Oberhuber, Cristina; Palacios, Daniel S.; Perruccio, Francesca; Piizzi, Grazia; Zurini, Mauro; Bialucha, Carl U.

doi:10.1021/acsmedchemlett.8b00254

Cited by 31 publications

(24 citation statements)

References 18 publications

(29 reference statements)

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“…Our recent studies of entities with deregulated MYC proteins, such as basal cell carcinomas [13], and Wnt pathway-driven conventional CRC [14], as well as our unpublished work on pancreatic ductal adenocarcinomas and a mouse model of lymphomagenesis indicate that targeting the positive feedback loop represents an approach with potential broader applicability in other tumor types beyond BRAF -mutant CRCs. Since several NAMPT inhibitor regimens are currently tested also in cancer clinical trials [52], [66], our findings may have rapid translational impact.…”

Section: Discussionmentioning

confidence: 84%

Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis

et al. 2019

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We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined Braf V600E and K-ras G12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF- mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.

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Section: Discussionmentioning

confidence: 84%

Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis

et al. 2019

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“…Inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT), an enzyme responsible for the conversion of nicotinamide to nicotinamide mononucleotide, showed efficacy in various preclinical and clinical studies, but their clinical utility has been limited by on-target and dose limiting toxicities such as thrombocytopenia and adverse GI effects. Therefore, researchers at Novartis looked for new NAMPT inhibitors that were suitable for vectorization as ADC payloads ( Figure 40 ) [ 60 ]. Using NAMPT-inhibitor X-ray cocrystal structures they determined the suitable exit vectors for linking.…”

Section: Adc Payloads and Their Attachment To The Linkermentioning

confidence: 99%

The Chemistry Behind ADCs

et al. 2021

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Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.

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“…Besides, additional examples of reported NAMPT inhibitors include GNE-617 [ 110 ] and GNE-618 (Genentech) [ 111 ], MV87 [ 112 ], A-1293201 and A-1326133 (AbbVie) [ 113 ], STF-118804 [ 114 ], LSN3154567 (Eli Lilly) [ 115 ], and antibody–drug conjugates (ADCs) with NAMPT inhibitors [ 116 , 117 ].…”

Section: Chemical Inhibitors Of Nad Biosynthesismentioning

confidence: 99%

“…Lastly, the single-dose administration (20 mg/kg) of two novel anti-c-KIT antibody–drug conjugates, with novel NAMPT inhibitors as payloads, efficiently blocked in vivo tumor proliferation in c-Kit-positive gastrointestinal stromal tumor GIST-T1 mouse xenografts [ 117 ]. In agreement with these results, another group reported the strong in vivo antitumor activity of NAMPTi-ADCs in xenograft models of AML, Hodgkin lymphoma, and non-Hodgkin lymphoma [ 116 ].…”

Section: In Vivo Studies Of Nad Production Inhibitors In Micementioning

confidence: 99%

Advances in NAD-Lowering Agents for Cancer Treatment

2021

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Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the “salvage pathway” of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.

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Nicotinamide Phosphoribosyltransferase Inhibitor as a Novel Payload for Antibody–Drug Conjugates

Cited by 31 publications

References 18 publications

Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis

Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis

The Chemistry Behind ADCs

Advances in NAD-Lowering Agents for Cancer Treatment

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