Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD⁺ biosynthesis via salvage of NAM formed from catabolism of NAD⁺ by proteins with NADase activity (e.g., PARPs, SIRTs, CD38). Depletion of NAD⁺ in aging, neurodegeneration, and metabolic disorders is addressed by NAD⁺ supplementation. Conversely, NAMPT inhibitors have been developed for cancer therapy: many discovered by phenotypic screening for cancer cell death have low nanomolar potency in cellular models. No NAMPT inhibitor is yet FDA-approved. The ability of inhibitors to act as NAMPT substrates may be associated with efficacy and toxicity. Some 3-pyridyl inhibitors become 4-pyridyl activators or "NAD⁺ boosters". NAMPT positive allosteric modulators (N-PAMs) and boosters may increase enzyme activity by relieving substrate/product inhibition. Binding to a "rear channel" extending from the NAMPT active site is key for inhibitors, boosters, and N-PAMs. A deeper understanding may fulfill the potential of NAMPT ligands to regulate cellular life and death.

01 Aug 2017·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT)

Q4 · MEDICINE

Article

Author: Doherty, George A ; Soni, Nirupama B ; Kovar, Peter J ; Buchanan, F Greg ; Frey, Robin R ; Longenecker, Kenton L ; Maag, David ; Tu, Noah ; Badagnani, Ilaria ; Sarris, Kathy A ; Cheng, Min ; Sorensen, Bryan K ; Guo, Jun ; Wilsbacher, Julie L ; Aguirre, Ana L ; Woller, Kevin ; Shrestha, Anurupa ; Pliushchev, Marina A ; Hansen, T Matthew ; Richardson, Paul L ; Curtin, Michael L ; Clark, Richard F ; Chiang, Gary G ; Algire, Mikkel A ; Raich, Diana ; Vasudevan, Anil ; Tse, Chris ; Marin, Violeta L ; Heyman, H Robin ; Michaelides, Michael R ; Korepanova, Alla V ; Cheng, Dong ; Sweis, Ramzi F

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

01 Jul 2017·Molecular Cancer TherapeuticsQ2 · MEDICINE

Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Q2 · MEDICINE

Article

Author: Trammell, Samuel A.J. ; Shi, Yan ; Gao, Wenqing ; Abraham, Vivek C. ; Buchanan, F. Gregory ; Brenner, Charles ; Wilsbacher, Julie L. ; Korepanova, Alla V. ; Koeniger, Stormy L. ; Michaelides, Michael R. ; Cheng, Min ; Hansen, T. Matthew ; Heyman, H. Robin ; Tang, Hua ; Cepa, Steven ; Rosenberg, Saul H. ; Badagnani, Ilaria ; Raich, Diana ; Longenecker, Kenton L. ; He, Yupeng ; Richardson, Paul L. ; Tse, Chris ; Towne, Danli L. ; Cheng, Dong ; Selvaraju, Sujatha ; Guo, Jun ; Sorensen, Bryan K. ; Chiang, Gary G. ; Clark, Richard F. ; Maag, David ; Kovar, Peter J. ; Curtin, Michael L. ; McLoughlin, Shaun M.

AbstractCancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.

100 Deals associated with A-1293201

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	AbbVie, Inc.	05 Apr 2024

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

A-1293201

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation