具有小鼠口服生物利用度的人乳酸脱氢酶细胞活性羟内酰胺抑制剂
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.
作者信息
Purkey Hans E, Robarge Kirk, Chen Jinhua, Chen Zhongguo, Corson Laura B, Ding Charles Z, DiPasquale Antonio G, Dragovich Peter S, Eigenbrot Charles, Evangelista Marie, Fauber Benjamin P, Gao Zhenting, Ge Hongxiu, Hitz Anna, Ho Qunh, Labadie Sharada S, Lai Kwong Wah, Liu Wenfeng, Liu Yajing, Li Chiho, Ma Shuguang, Malek Shiva, O'Brien Thomas, Pang Jodie, Peterson David, Salphati Laurent, Sideris Steve, Ultsch Mark, Wei BinQing, Yen Ivana, Yue Qin, Zhang Huihui, Zhou Aihe
机构信息
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
出版信息
ACS Med Chem Lett. 2016 Aug 26;7(10):896-901. doi: 10.1021/acsmedchemlett.6b00190. eCollection 2016 Oct 13.
Abstract
A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC in a MiaPaca2 cell line. Optimization of the series led to , a potent cell active molecule (MiaPaca2 IC = 0.67 μM) that also possessed good exposure when dosed orally to mice.
摘要
一系列三取代羟基内酰胺被鉴定为人类乳酸脱氢酶A的强效酶抑制剂和细胞抑制剂。利用基于结构的设计和物理性质优化，在MiaPaca2细胞系中发现了多种乳酸IC小于10 μM的抑制剂。该系列的优化产生了一种强效的细胞活性分子（MiaPaca2 IC = 0.67 μM），该分子在口服给药于小鼠时也具有良好的暴露性。
相似文献
1
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.
ACS Med Chem Lett. 2016 Aug 26;7(10):896-901. doi: 10.1021/acsmedchemlett.6b00190. eCollection 2016 Oct 13.
2
Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase.
Bioorg Med Chem Lett. 2022 Mar 1;59:128576. doi: 10.1016/j.bmcl.2022.128576. Epub 2022 Jan 19.
3
Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi: 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1.
4
Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2014 Dec 15;24(24):5683-5687. doi: 10.1016/j.bmcl.2014.10.067. Epub 2014 Oct 27.
5
Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2015 Jan 1;25(1):75-82. doi: 10.1016/j.bmcl.2014.11.008. Epub 2014 Nov 10.
6
Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line.
Bioorg Med Chem Lett. 2016 Jan 1;26(1):72-5. doi: 10.1016/j.bmcl.2015.11.025. Epub 2015 Nov 10.
7
Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines.
ACS Med Chem Lett. 2015 Nov 2;6(12):1190-4. doi: 10.1021/acsmedchemlett.5b00322. eCollection 2015 Dec 10.
8
Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.
ACS Med Chem Lett. 2015 Mar 2;6(4):413-8. doi: 10.1021/ml500474d. eCollection 2015 Apr 9.
9
Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation.
J Med Chem. 2012 Apr 12;55(7):3285-306. doi: 10.1021/jm201734r. Epub 2012 Mar 26.
10
Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.
Bioorg Med Chem Lett. 2018 Jul 1;28(12):2159-2164. doi: 10.1016/j.bmcl.2018.05.014. Epub 2018 May 8.
引用本文的文献
1
Targeting Lactate: An Emerging Strategy for Macrophage Regulation in Chronic Inflammation and Cancer.
Biomolecules. 2024 Sep 24;14(10):1202. doi: 10.3390/biom14101202.
2
Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.
Eur J Med Chem. 2024 Sep 5;275:116598. doi: 10.1016/j.ejmech.2024.116598. Epub 2024 Jun 17.
3
Exploring the Key Amino Acid Residues Surrounding the Active Center of Lactate Dehydrogenase A for the Development of Ideal Inhibitors.
Molecules. 2024 Apr 28;29(9):2029. doi: 10.3390/molecules29092029.
4
Exploration of a Large Virtual Chemical Space: Identification of Potent Inhibitors of Lactate Dehydrogenase-A against Pancreatic Cancer.
J Chem Inf Model. 2023 Feb 13;63(3):1028-1043. doi: 10.1021/acs.jcim.2c01544. Epub 2023 Jan 16.
5
Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics.
Front Immunol. 2022 Dec 22;13:955476. doi: 10.3389/fimmu.2022.955476. eCollection 2022.
6
Peptide-based LDH5 inhibitors enter cancer cells and impair proliferation.
Cell Mol Life Sci. 2022 Nov 27;79(12):606. doi: 10.1007/s00018-022-04633-3.
7
The multiple roles of LDH in cancer.
Nat Rev Clin Oncol. 2022 Dec;19(12):749-762. doi: 10.1038/s41571-022-00686-2. Epub 2022 Oct 7.
8
MYCN and Metabolic Reprogramming in Neuroblastoma.
Cancers (Basel). 2022 Aug 25;14(17):4113. doi: 10.3390/cancers14174113.
9
Genetic and Drug Inhibition of LDH-A: Effects on Murine Gliomas.
Cancers (Basel). 2022 May 6;14(9):2306. doi: 10.3390/cancers14092306.
10
Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?
Int J Mol Sci. 2021 Dec 21;23(1):48. doi: 10.3390/ijms23010048.
本文引用的文献
1
Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
Nat Chem Biol. 2016 Oct;12(10):779-86. doi: 10.1038/nchembio.2143. Epub 2016 Aug 1.
2
Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line.
Bioorg Med Chem Lett. 2016 Jan 1;26(1):72-5. doi: 10.1016/j.bmcl.2015.11.025. Epub 2015 Nov 10.
3
Recent Update on Human Lactate Dehydrogenase Enzyme 5 (hLDH5) Inhibitors: A Promising Approach for Cancer Chemotherapy.
J Med Chem. 2016 Jan 28;59(2):487-96. doi: 10.1021/acs.jmedchem.5b00168. Epub 2015 Sep 4.
4
Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2014 Dec 15;24(24):5683-5687. doi: 10.1016/j.bmcl.2014.10.067. Epub 2014 Oct 27.
5
Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2015 Jan 1;25(1):75-82. doi: 10.1016/j.bmcl.2014.11.008. Epub 2014 Nov 10.
6
Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Bioorg Med Chem Lett. 2014 Aug 15;24(16):3764-71. doi: 10.1016/j.bmcl.2014.06.076. Epub 2014 Jul 1.
7
Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells.
Cell Metab. 2014 May 6;19(5):795-809. doi: 10.1016/j.cmet.2014.03.003. Epub 2014 Apr 10.
8
Lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy.
Br J Cancer. 2014 Apr 29;110(9):2217-23. doi: 10.1038/bjc.2014.158. Epub 2014 Apr 8.
9
Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells.
Cancer Metab. 2013 Sep 6;1(1):19. doi: 10.1186/2049-3002-1-19.
10
A novel method for high throughput lipophilicity determination by microscale shake flask and liquid chromatography tandem mass spectrometry.
Comb Chem High Throughput Screen. 2013 Dec;16(10):817-25. doi: 10.2174/1386207311301010007.
Zotero 插件