基于结构的强效 Bcl-2/Bcl-xL 抑制剂的设计及其在体内的抗肿瘤活性。
Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.
机构信息
Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-0934, USA.
出版信息
J Med Chem. 2012 Jul 12;55(13):6149-61. doi: 10.1021/jm300608w. Epub 2012 Jul 2.
Abstract
Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
摘要
Bcl-2 和 Bcl-xL 是凋亡的关键调节因子，也是有吸引力的癌症治疗靶点。我们设计并优化了一类含有 4,5-二苯基-1H-吡咯-3-羧酸核心结构的 Bcl-2 和 Bcl-xL 的小分子抑制剂。一个先导化合物 12 与 Bcl-xL 形成的 1.4 Å 分辨率晶体结构为我们的优化提供了基础。最有效的化合物 14 和 15 以亚纳摩尔的 K(i)值与 Bcl-2 和 Bcl-xL 结合，并且在功能测定中是 Bcl-2 和 Bcl-xL 的有效拮抗剂。化合物 14 和 15 在多种小细胞肺癌细胞系中以低纳摩尔的 IC(50)值抑制细胞生长，并在低至 10 nM 的浓度下诱导癌细胞强烈凋亡。化合物 14 在人类癌症的动物模型中也表现出很强的抗肿瘤活性。
相似文献
1
Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.
J Med Chem. 2012 Jul 12;55(13):6149-61. doi: 10.1021/jm300608w. Epub 2012 Jul 2.
2
Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold.
J Med Chem. 2012 May 24;55(10):4664-82. doi: 10.1021/jm300178u. Epub 2012 May 10.
3
Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression.
J Med Chem. 2012 Oct 11;55(19):8502-14. doi: 10.1021/jm3010306. Epub 2012 Oct 2.
4
Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
J Med Chem. 2007 Feb 22;50(4):641-62. doi: 10.1021/jm061152t. Epub 2007 Jan 26.
5
BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo.
PLoS One. 2014 Jun 5;9(6):e99404. doi: 10.1371/journal.pone.0099404. eCollection 2014.
6
Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3951-6. doi: 10.1016/j.bmcl.2012.04.106. Epub 2012 Apr 30.
7
Development of 3-phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide compounds as inhibitors of antiapoptotic Bcl-2 family proteins.
ChemMedChem. 2014 Jul;9(7):1436-52. doi: 10.1002/cmdc.201400058. Epub 2014 Apr 29.
8
Discovery of PROTAC BCL-X degraders as potent anticancer agents with low on-target platelet toxicity.
Eur J Med Chem. 2020 Apr 15;192:112186. doi: 10.1016/j.ejmech.2020.112186. Epub 2020 Feb 27.
9
Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
J Med Chem. 2013 Dec 12;56(23):9635-45. doi: 10.1021/jm401170c. Epub 2013 Dec 2.
10
Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X and BCL-2.
J Med Chem. 2021 May 13;64(9):5447-5469. doi: 10.1021/acs.jmedchem.0c01771. Epub 2021 Apr 27.
引用本文的文献
1
Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL.
Nat Commun. 2024 Mar 29;15(1):2743. doi: 10.1038/s41467-024-46922-4.
2
Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1-imidazole-4-carboxylic Acids and 1,5-Diaryl-1-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors.
Molecules. 2021 Oct 14;26(20):6203. doi: 10.3390/molecules26206203.
3
Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer.
Biochem Soc Trans. 2021 Nov 1;49(5):2381-2395. doi: 10.1042/BST20210749.
4
Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer.
Cells. 2020 May 21;9(5):1287. doi: 10.3390/cells9051287.
5
Identification of molecular features necessary for selective inhibition of B cell lymphoma proteins using machine learning techniques.
Mol Divers. 2019 Feb;23(1):55-73. doi: 10.1007/s11030-018-9856-x. Epub 2018 Jul 12.
6
Selectivity by small-molecule inhibitors of protein interactions can be driven by protein surface fluctuations.
PLoS Comput Biol. 2015 Feb 23;11(2):e1004081. doi: 10.1371/journal.pcbi.1004081. eCollection 2015 Feb.
7
3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation.
J Med Chem. 2014 May 22;57(10):4111-33. doi: 10.1021/jm500010b. Epub 2014 May 7.
8
Mitochondria are the primary target in the induction of apoptosis by chiral ruthenium(II) polypyridyl complexes in cancer cells.
J Biol Inorg Chem. 2014 Mar;19(3):335-48. doi: 10.1007/s00775-013-1069-2. Epub 2013 Nov 28.
9
Cell death and the mitochondria: therapeutic targeting of the BCL-2 family-driven pathway.
Br J Pharmacol. 2014 Apr;171(8):1973-87. doi: 10.1111/bph.12431.
10
A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.
J Med Chem. 2013 Apr 11;56(7):3048-3067. doi: 10.1021/jm4001105. Epub 2013 Mar 22.
本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold.
J Med Chem. 2012 May 24;55(10):4664-82. doi: 10.1021/jm300178u. Epub 2012 May 10.
3
Hallmarks of cancer: the next generation.
Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
4
Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
J Med Chem. 2011 Mar 24;54(6):1914-26. doi: 10.1021/jm101596e. Epub 2011 Mar 2.
5
Phaser crystallographic software.
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. doi: 10.1107/S0021889807021206. Epub 2007 Jul 13.
6
BCL-2 family antagonists for cancer therapy.
Nat Rev Drug Discov. 2008 Dec;7(12):989-1000. doi: 10.1038/nrd2658.
7
Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
J Med Chem. 2008 Nov 13;51(21):6902-15. doi: 10.1021/jm800669s. Epub 2008 Oct 8.
8
ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.
Cancer Res. 2008 May 1;68(9):3421-8. doi: 10.1158/0008-5472.CAN-07-5836.
9
Therapeutic targeting of apoptosis pathways in cancer.
Curr Opin Oncol. 2008 Jan;20(1):97-103. doi: 10.1097/CCO.0b013e3282f310f6.
10
Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family.
Cell Death Differ. 2007 Sep;14(9):1711-3. doi: 10.1038/sj.cdd.4402178. Epub 2007 Jun 15.
Zotero 插件