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Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
- Title
- Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
- Authors
- Kim, Minjee; Kim, Hyeyoung; Kang, Bu-Gyeong; Lee, Jooyoung; Kim, Taegun; Lee, Hwanho; Jung, Jane; Oh, Myung Joon; Seo, Seungyoon; Ryu, Myung-Jeom; Sung, Yeojin; Lee, Yunji; Yeom, Jeonghun; Han, Gyoonhee; Cha, Sun-Shin; Jung, Hosung; Kim, Hyun Seok
- Ewha Authors
- 차선신
- SCOPUS Author ID
- 차선신
- Issue Date
- 2023
- Journal Title
- THERANOSTICS
- ISSN
- 1838-7640
- Citation
- THERANOSTICS vol. 13, no. 14, pp. 5075 - 5098
- Keywords
- Synthetic lethality; NAMPT inhibitor; Epithelial-to-mesenchymal transition (EMT); Wallerian degeneration; Chemotherapy-induced peripheral neuropathy (CIPN)
- Publisher
- IVYSPRING INT PUBL
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN.Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo.Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio.Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.
- DOI
- 10.7150/thno.85356
- Appears in Collections:
- 자연과학대학 > 화학·나노과학전공 > Journal papers
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