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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

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 nico...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526665/
https://www.ncbi.nlm.nih.gov/pubmed/37771778
http://dx.doi.org/10.7150/thno.85356
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author 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
author_facet 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
author_sort Kim, Minjee
collection PubMed
description 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.
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spelling pubmed-105266652023-09-28 Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy 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 Theranostics Research Paper 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. Ivyspring International Publisher 2023-09-11 /pmc/articles/PMC10526665/ /pubmed/37771778 http://dx.doi.org/10.7150/thno.85356 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
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
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
title_full Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
title_fullStr Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
title_full_unstemmed Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
title_short Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
title_sort discovery of a novel nampt inhibitor that selectively targets naprt-deficient emt-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526665/
https://www.ncbi.nlm.nih.gov/pubmed/37771778
http://dx.doi.org/10.7150/thno.85356
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