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乳酸脱氢酶A同工型选择性变构抑制的结构证据

Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A.

作者信息

Friberg Anders, Rehwinkel Hartmut, Nguyen Duy, Pütter Vera, Quanz Maria, Weiske Jörg, Eberspächer Uwe, Heisler Iring, Langer Gernot

机构信息

Bayer AG, Pharmaceuticals, R&D, Müllerstrasse 178, 13342 Berlin, Germany.

Bayer AG, Pharmaceuticals, R&D, Aprather Weg 18A, 42113 Wuppertal, Germany.

出版信息

ACS Omega. 2020 May 27;5(22):13034-13041. doi: 10.1021/acsomega.0c00715. eCollection 2020 Jun 9.

DOI:10.1021/acsomega.0c00715
PMID:32548488
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7288559/
Abstract

Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumors, thereby sustaining high glycolysis rates, tumor growth, and chemoresistance. High-throughput screening resulted in the identification of phthalimide and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors, selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization experiments confirmed target engagement in addition to demonstrating binding to a novel allosteric binding site present in all four LDHA subunits of the LDH5 homotetramer.

摘要

乳酸脱氢酶A（LDHA）在肿瘤中经常过度表达，从而维持高糖酵解速率、肿瘤生长和化疗耐药性。高通量筛选鉴定出邻苯二甲酰亚胺和二苯并呋喃衍生物为新型乳酸脱氢酶抑制剂，可选择性抑制LDHA同工酶的活性。共结晶实验除了证明与LDH5同四聚体的所有四个LDHA亚基中存在的新型变构结合位点结合外，还证实了靶点结合。

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本文引用的文献

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Oncoimmunology. 2020 Feb 26;9(1):1731942. doi: 10.1080/2162402X.2020.1731942. eCollection 2020.
2
Identification of human lactate dehydrogenase A inhibitors with anti-osteosarcoma activity through cell-based phenotypic screening.通过基于细胞的表型筛选鉴定具有抗骨肉瘤活性的人乳酸脱氢酶 A 抑制剂。
Bioorg Med Chem Lett. 2020 Feb 15;30(4):126909. doi: 10.1016/j.bmcl.2019.126909. Epub 2019 Dec 18.
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Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities.
抑制单体人 l-乳酸脱氢酶组装成催化活性同源四聚体的肽减少培养细胞中乳酸的合成。
Protein Sci. 2024 Oct;33(10):e5161. doi: 10.1002/pro.5161.
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Exploring the Key Amino Acid Residues Surrounding the Active Center of Lactate Dehydrogenase A for the Development of Ideal Inhibitors.探讨乳酸脱氢酶 A 活性中心周围的关键氨基酸残基，以开发理想的抑制剂。
Molecules. 2024 Apr 28;29(9):2029. doi: 10.3390/molecules29092029.
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Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription.组蛋白乳酰化在代谢重编程和表观遗传重排中架起桥梁，推动致癌作用发生：代谢物为致癌转录提供燃料。
Clin Transl Med. 2024 Mar;14(3):e1614. doi: 10.1002/ctm2.1614.
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Deciphering Evolutionary Trajectories of Lactate Dehydrogenases Provides New Insights into Allostery.解析乳酸脱氢酶的进化轨迹为变构作用提供了新的见解。
Mol Biol Evol. 2023 Oct 4;40(10). doi: 10.1093/molbev/msad223.
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A study of the interaction space of two lactate dehydrogenase isoforms (LDHA and LDHB) and some of their inhibitors using proteochemometrics modeling.一项使用蛋白质化学计量学模型对两种乳酸脱氢酶同工酶（LDHA和LDHB）及其一些抑制剂的相互作用空间进行的研究。
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