Apogossypol Derivatives As Antagonists of Antiapoptotic Bcl-2 Family Proteins

Overview

Journal Mol Cancer Ther

Date 2009 Apr 18

PMID 19372563

Citations 26

Authors

Jun Wei

Shinichi Kitada

Michele F Rega

Aras Emdadi

Hongbin Yuan

Jason Cellitti

John L Stebbins

Dayong Zhai

Jiazhi Sun

Li Yang

Russell Dahl

Ziming Zhang

Bainan Wu

Si Wang

Tyler A Reed

Hong-Gang Wang

Nicholas Lawrence

Said Sebti

John C Reed

Maurizio Pellecchia

Affiliations

Soon will be listed here.

Abstract

Guided by a combination of nuclear magnetic resonance binding assays and computational docking studies, we synthesized a library of 5,5' substituted Apogossypol derivatives as potent Bcl-XL antagonists. Each compound was subsequently tested for its ability to inhibit Bcl-XL in an in vitro fluorescence polarization competition assay and exert single-agent proapoptotic activity in human cancer cell lines. The most potent compound BI79D10 binds to Bcl-XL, Bcl-2, and Mcl-1 with IC50 values of 190, 360, and 520 nmol/L, respectively, and potently inhibits cell growth in the H460 human lung cancer cell line with an EC50 value of 680 nmol/L, expressing high levels of Bcl-2. BI79D10 also effectively induces apoptosis of the RS11846 human lymphoma cell line in a dose-dependent manner and shows little cytotoxicity against bax-/-bak-/- mouse embryonic fibroblast cells, in which antiapoptotic Bcl-2 family proteins lack a cytoprotective phenotype, implying that BI79D10 has little off-target effects. BI79D10 displays in vivo efficacy in transgenic mice, in which Bcl-2 is overexpressed in splenic B cells. Together with its improved plasma and microsomal stability relative to Apogossypol, BI79D10 represents a lead compound for the development of novel apoptosis-based therapies for cancer.

Citing Articles

Recombinant MDA-7/IL24 Suppresses Prostate Cancer Bone Metastasis through Downregulation of the Akt/Mcl-1 Pathway.

Pradhan A, Bhoopathi P, Talukdar S, Shen X, Emdad L, Das S Mol Cancer Ther. 2018; 17(9):1951-1960.

PMID: 29934341 PMC: 7598934. DOI: 10.1158/1535-7163.MCT-17-1002.

Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis.

Yu X, Li W, Xia Z, Xie L, Ma X, Liang Q BMC Cancer. 2017; 17(1):449.

PMID: 28659182 PMC: 5490225. DOI: 10.1186/s12885-017-3442-y.

Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.

Antony P, Vijayan R Drug Des Devel Ther. 2016; 10:1399-410.

PMID: 27110097 PMC: 4835113. DOI: 10.2147/DDDT.S103216.

Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline.

Quinn B, Dash R, Sarkar S, Azab B, Bhoopathi P, Das S Cancer Res. 2015; 75(11):2305-15.

PMID: 26032425 PMC: 4453003. DOI: 10.1158/0008-5472.CAN-14-3013.

Olive leaf extract inhibits lead poisoning-induced brain injury.

Wang Y, Wang S, Cui W, He J, Wang Z, Yang X Neural Regen Res. 2014; 8(22):2021-9.

PMID: 25206510 PMC: 4146066. DOI: 10.3969/j.issn.1673-5374.2013.22.001.

References

Reed J . Bcl-2 family proteins. Oncogene. 1999; 17(25):3225-36. DOI: 10.1038/sj.onc.1202591. View

Reed J . Dysregulation of apoptosis in cancer. J Clin Oncol. 1999; 17(9):2941-53. DOI: 10.1200/JCO.1999.17.9.2941. View

Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T . Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol. 2001; 3(2):173-82. DOI: 10.1038/35055085. View

Becattini B, Kitada S, Leone M, Monosov E, Chandler S, Zhai D . Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol. 2004; 11(3):389-95. DOI: 10.1016/j.chembiol.2004.02.020. View

Coward L, Gorman G, Noker P, Kerstner-Wood C, Pellecchia M, Reed J . Quantitative determination of apogossypol, a pro-apoptotic analog of gossypol, in mouse plasma using LC/MS/MS. J Pharm Biomed Anal. 2006; 42(5):581-6. DOI: 10.1016/j.jpba.2006.05.020. View

Wang J, Liu D, Zhang Z, Shan S, Han X, Srinivasula S . Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2000; 97(13):7124-9. PMC: 16510. DOI: 10.1073/pnas.97.13.7124. View

Teschner M, Henn C, Vollhardt H, Reiling S, Brickmann J . Texture mapping: a new tool for molecular graphics. J Mol Graph. 1994; 12(2):98-105. DOI: 10.1016/0263-7855(94)80074-x. View

Ramjaun A, Tomlinson S, Eddaoudi A, Downward J . Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene. 2006; 26(7):970-81. DOI: 10.1038/sj.onc.1209852. View

Reed J . Apoptosis-based therapies. Nat Rev Drug Discov. 2002; 1(2):111-21. DOI: 10.1038/nrd726. View

10.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

11.

Adams J, Cory S . The Bcl-2 protein family: arbiters of cell survival. Science. 1998; 281(5381):1322-6. DOI: 10.1126/science.281.5381.1322. View

12.

Shelley M, Hartley L, Groundwater P, FISH R . Structure-activity studies on gossypol in tumor cell lines. Anticancer Drugs. 2000; 11(3):209-16. DOI: 10.1097/00001813-200003000-00009. View

13.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

14.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

15.

Jones G, Willett P, Glen R, Leach A, Taylor R . Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997; 267(3):727-48. DOI: 10.1006/jmbi.1996.0897. View

16.

Zhai D, Jin C, Shiau C, Kitada S, Satterthwait A, Reed J . Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther. 2008; 7(6):1639-46. PMC: 2614397. DOI: 10.1158/1535-7163.MCT-07-2373. View

17.

Sattler M, Liang H, Nettesheim D, Meadows R, Harlan J, Eberstadt M . Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science. 1997; 275(5302):983-6. DOI: 10.1126/science.275.5302.983. View

18.

Katsumata M, Siegel R, Louie D, Miyashita T, Tsujimoto Y, Nowell P . Differential effects of Bcl-2 on T and B cells in transgenic mice. Proc Natl Acad Sci U S A. 1992; 89(23):11376-80. PMC: 50553. DOI: 10.1073/pnas.89.23.11376. View

19.

Zhang M, Liu H, Guo R, Ling Y, Wu X, Li B . Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Biochem Pharmacol. 2003; 66(1):93-103. DOI: 10.1016/s0006-2952(03)00248-x. View

20.

Eldridge M, MURRAY C, Auton T, Paolini G, Mee R . Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des. 1997; 11(5):425-45. DOI: 10.1023/a:1007996124545. View