What is the potential of NAMPT, a target in the tumor field?

Potential targets with clinical advantages are the targets that innovative drug R&D companies are looking for
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However, in the face of today's global new drug research and development situation, it is difficult to take an excellent potential target as one's own, especially in the most competitive oncology field
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So, whether new targets are followed with high risk, and whether old targets can solve existing clinical problems are all choices that new drug developers have to make
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Such as NAMPT, what is the potential of this tumor target that has undergone certain development? How to carry out product follow-up based on existing drug characteristics? Why do domestic pharmaceutical companies have certain favors for it? 01 NAMPT/Discovery & Distribution & Function In 1994, the encoding gene was first screened from the cDNA gene library of activated human peripheral blood lymphocytes, which was named PBEF at that time; in 2001, it was found that PBEF has NAMPT (nicotinamide phosphoribosyltransferase) in cells ) activity, so it is also called NAMPT; in 2005, it was gradually confirmed that PBEF, NAMPT and visfatin are actually the same protein molecule encoded by a gene
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NAMPT is widely expressed in human bone marrow, liver, muscle, visceral fat and other organs and tissues, and expressed in immune cells, cardiomyocytes, fibroblasts, nerve cells and other cells, but astrocytes do not express NAMPT, which shows that this Proteins play important roles in both physiological and pathological conditions
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Intracellular NAMPT is mainly distributed in the cytoplasm, nucleus and mitochondria, uses ATP as an activator, plays its biological function as a rate-limiting enzyme in the NAD salvage synthesis pathway, and participates in energy metabolism, reductive biosynthesis, antioxidant reactions, cellular live and die
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Extracellular, NAMPT acts as a growth factor, such as in the presence of stem cell factor and interleukin 7, NAMPT can promote the formation of pre-B cell clones and facilitate B cell maturation, which is also the origin of its original name as PBEF
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Both intracellular and extracellular NAMPT in tumor patients are significantly higher than those in normal controls.
Studies have shown that the content of NAMPT in patients with colorectal cancer, gastric cancer, melanoma, glioma, and breast cancer is significantly increased
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02 Detailing the metabolic pathway of NAMPT Through the above introduction to the discovery, distribution, and basic biological functions of NAMPT, the following focuses on the key markers around NAMPT and their interactions
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At this stage, most of the literature on NAMPT is connected with NAD, which is related to the biological characteristics of NAD, and at the same time, it is related to epigenetics and tumor microenvironment
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NAMPT converts NAM to NMN by promoting the reversible binding of the ribose component in 5-phosphoribose-1-pyrophosphate (PRPP) to NAM, which in turn converts NMN to NAD under the action of NMNAT
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If the intracellular NAMPT content is insufficient or the enzymatic activity is reduced, the synthesis pathway of NAD and the cellular metabolism that NAD participates in are blocked, resulting in a decline in the ability of tumor cells to produce ATP and 1,3-diphosphoglycerate and other biological macromolecules.
Impaired tolerance to exogenous glucose deficiency
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At the same time, NAMPT indirectly affects NAD-dependent enzymatic activity by synthesizing NAD, thereby regulating tumor cell metabolism and NAD synthesis capacity
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The signal pathway is shown in the figure below
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03 Statistics on the development of NAMPT inhibitors The global research and development of new drugs is gradually showing a state of congestion on the track.
Any promising target will be favored by researchers in order to gain a certain market opportunity
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The development of NAMPT inhibitors started many years ago, and some related varieties entered clinical research, but due to the safety problems presented by some varieties, the trials and projects were stopped
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The varieties developed in the early stage mainly include the following: FK866, CHS828, CB30865, IS001, the highest clinical phase II; among them, FK866 has more research contents, also known as Daporinad, and IS001 is its analog
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FK866, developed by Apoxis, was acquired by Topo Target in 2007 and merged into Onxeo in 2014; the compound was discovered from screening and can effectively induce apoptosis in human hepatoma cells HepG2 with IC50 of about 1nM
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In the enzyme kinetics experiment, the maximum reaction rate of NAMPT to the substrate NAM was 282pM, and the Km was 1.
8μM.
FK866 dose-dependently decreased the Vmax value of the enzyme and slightly increased the Km value
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The inhibition constant Ki of FK866 for the enzyme-substrate complex was 0.
4 nM and the inhibition constant Ki for the enzyme was 0.
3 nM
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The affinity of ligands and receptors is shown in the figure below
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The clinical development of FK866 mainly targets B-cell chronic lymphocytic leukemia, cutaneous T-cell lymphoma, and melanoma
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The completed clinical trials are shown in the table below
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In addition to the 4 varieties introduced in the above-mentioned documents, the NAMPT inhibitors currently entering the clinical stage include KPT-9274 in clinical phase II (which has been developed in cooperation with domestic Antengene), and clinical phase I OT-82; There are relatively many preclinical varieties, and nearly a dozen varieties have been publicly reported
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KPT-9274, developed by Karyopharm, is mainly used for the treatment of non-Hodgkin B-cell lymphoma and solid tumors
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In May 2018, Karyopharm Therapeutics signed an agreement with Antengene under which Antengene will have the right to develop and commercialize KPT-9274 for all oncology indications in China, South Korea and ASEAN member countries
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It should be noted, however, that KPT-9274 is the first-in-class oral inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT), a signaling protein that regulates multiple basal cells processes, including intracellular trafficking, cell division, cell morphology and motility, cell survival, immune defense and development of cancer
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PAK4 interacts with multiple major signaling molecules involved in cancer development, including beta-catenin, CDC42, Raf-1, BAD and myosin light chain
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NAMPT is a pleiotropic protein that performs multiple functions in and out of cells, such as enzymes, cytokines, growth factors and hormones, and can form complexes with PAK4 in cells
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In murine tumor models, ATG-019 combined with anti-PD-1 therapy showed better anti-tumor effect than anti-PD-1 monotherapy, indicating that the combination therapy has the potential to treat anti-PD-1-resistant tumor patients
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04 Summary To sum up, this is the general situation of NAMPT target and its drug development progress, which can be summarized as follows: 1) The target development time is not long, the degree of development is not high, and there is value for continued development; 2) The target The biological characteristics of the drug need to be further explored in order to better understand its function; 3) The degree of drug development is not high, and it has not yet caused a large number of pharmaceutical companies in the industry to enter the track; 4) Domestic pharmaceutical companies have chosen to jointly develop , it is worth pondering, digging, and following up
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