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3-硝基吡啶类似物作为新型微管靶向剂。

3-nitropyridine analogues as novel microtubule-targeting agents.

机构信息

4AZA Biosciences, Leuven, Belgium.

Interface Valorisation Platform (IVAP), KU Leuven, Leuven, Belgium.

出版信息

PLoS One. 2024 Nov 7;19(11):e0307153. doi: 10.1371/journal.pone.0307153. eCollection 2024.

DOI:10.1371/journal.pone.0307153
PMID:39509402
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11542830/
Abstract

Microtubule-targeting agents are an important class of anti-cancer drugs; their full potential is however not realized because of significant myelotoxicity and neurotoxicity. We here report 3-nitropyridine analogues as a novel group of microtubule-targeting agents with potent anti-cancer effects against a broad range of cancer types. We show that these 3-nitropyridines induce cell cycle arrest in the G2-M phase and inhibit tubulin polymerization by interacting with tubulin. Determination of the tubulin-4AZA2996 structure by X-ray crystallography demonstrated that this class of compounds binds to the colchicine-site of tubulin. Furthermore, the anti-cancer effect was demonstrated both in vitro and in vivo in a murine heterotopic xenograft model of colon cancer. When administered intravenously, 4AZA2891 effectively inhibited cancer growth. Whereas 3-nitropyridine compounds do not induce myelotoxicity at pharmacological doses, the neurotoxicity associated with microtubule-targeting agents is still present.

摘要

微管靶向剂是一类重要的抗癌药物；然而，由于其严重的骨髓毒性和神经毒性，其潜力尚未得到充分发挥。我们在这里报告了 3-硝基吡啶类似物作为一类新的微管靶向剂，对广泛的癌症类型具有强大的抗癌作用。我们表明，这些 3-硝基吡啶通过与微管蛋白相互作用诱导细胞周期在 G2-M 期停滞，并抑制微管蛋白聚合。X 射线晶体学测定的微管蛋白-4AZA2996 结构表明，这类化合物结合在微管蛋白的秋水仙碱结合部位。此外，在结肠癌的小鼠异位异种移植模型中，无论是在体外还是体内，都证明了抗癌作用。当静脉内给药时，4AZA2891 有效地抑制了癌症的生长。虽然 3-硝基吡啶化合物在药理学剂量下不会引起骨髓毒性，但与微管靶向剂相关的神经毒性仍然存在。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/29fc6b69fba1/pone.0307153.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/597a26d413b3/pone.0307153.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/5ddfa17a71f2/pone.0307153.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/ff4f467bc55f/pone.0307153.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/8ff040073190/pone.0307153.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/d23650d16910/pone.0307153.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/29fc6b69fba1/pone.0307153.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/597a26d413b3/pone.0307153.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/5ddfa17a71f2/pone.0307153.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/ff4f467bc55f/pone.0307153.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/8ff040073190/pone.0307153.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/d23650d16910/pone.0307153.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a292/11542830/29fc6b69fba1/pone.0307153.g006.jpg

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