title: Bcl-2 antagonists: a proof of concept for CLL therapy.
abstract: Defective apoptosis is a fundamental hallmark feature of CLL biology and is a major target of cancer therapy development. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. While several approaches were considered to selectively inhibit Bcl-2 family anti-apoptotic proteins, the discovery that gossypol binds and antagonizes anti-apoptotic effect of Bcl-2 family proteins was a major breakthrough in identifying specific Bcl-2 antagonists. The concept of mimicking BH3 domain emphasized the importance of Bcl-2 family-targeted therapy that can modulate the function of anti-apoptotic proteins. Although parent compound gossypol did not sustain in the clinic, its structural modifications led to the development of additional analogues that demonstrated improved efficacy and reduced toxicity in preclinical and clinical investigations. Proof of concept of this hypothesis was demonstrated by structure based BH3 mimetic ABT-737 that has shown greater cytotoxicity towards CLL cells both in pre-clinical models and clinical trials. Its oral compound ABT-263 has demonstrated the substantial susceptibility of chronic lymphocytic leukemia cells through Bcl-2 inhibition. Collectively, results of a Phase I Study of Navitoclax (ABT-263) in patients with relapsed or refractory disease warrants Bcl-2 as a valid therapeutic target in CLL. Importantly, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Mcl-1, Bcl-2 and Bcl-XL.
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, kbalakr@mdanderson.org.
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2
references.citation: Cancer Res. 2008 May 1;68(9):3413-20
references.pmid: 18451169
references.citation: Life Sci. 1995;57(1):61-7
references.pmid: 7596222
references.citation: J Med Chem. 2003 Sep 25;46(20):4259-64
references.pmid: 13678404
references.citation: J Biol Chem. 2012 Jan 2;287(1):68-80
references.pmid: 22052903
references.citation: Blood. 2008 Sep 1;112(5):1971-80
references.pmid: 18566329
references.citation: Eur J Cancer. 1973 Mar;9(3):215-21
references.pmid: 4787856
references.citation: Leuk Lymphoma. 2013 May;54(5):1097-100
references.pmid: 22866921
references.citation: Blood. 2005 Jul 15;106(2):408-18
references.pmid: 15797997
references.citation: Cancer Res. 2007 Jan 15;67(2):782-91
references.pmid: 17234790
references.citation: Clin Cancer Res. 2009 Jan 1;15(1):150-9
references.pmid: 19118042
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Contraception. 1995 Dec;52(6):389-95
references.pmid: 8749604
references.citation: Cancer Res. 1984 Jan;44(1):35-8
references.pmid: 6690046
references.citation: Blood. 2012 Jun 21;119(25):6089-98
references.pmid: 22446485
references.citation: Cancer Chemother Pharmacol. 2008 Jan;61(1):63-73
references.pmid: 17356822
references.citation: Cancer Biol Ther. 2010 Nov 1;10(9):903-17
references.pmid: 20855960
references.citation: Drugs. 1989 Sep;38(3):333-41
references.pmid: 2680434
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14907-12
references.pmid: 16997913
references.citation: Clin Cancer Res. 2008 Dec 15;14(24):8295-301
references.pmid: 19088047
references.citation: Mol Cancer Ther. 2009 Apr;8(4):904-13
references.pmid: 19372563
references.citation: Semin Oncol. 1992 Dec;19(6):646-62
references.pmid: 1361079
references.citation: J Neurooncol. 1999 May;43(1):79-86
references.pmid: 10448875
references.citation: Cancer Cell. 2006 Nov;10(5):389-99
references.pmid: 17097561
references.citation: Nat Med. 2013 Feb;19(2):202-8
references.pmid: 23291630
references.citation: Mol Cell Biol. 2009 Dec;29(23):6149-69
references.pmid: 19805519
references.citation: Cell Death Differ. 2006 Aug;13(8):1419-21
references.pmid: 16645636
references.citation: Blood. 2008 Jun 1;111(11):5350-8
references.pmid: 18292288
references.citation: J Biol Chem. 2010 Aug 13;285(33):25570-81
references.pmid: 20529838
references.citation: Eur J Med Chem. 2004 Jul;39(7):619-24
references.pmid: 15236842
references.citation: Int J Androl. 1982 Apr;5(2):205-9
references.pmid: 7107034
references.citation: Int J Androl. 1998 Feb;21(1):8-12
references.pmid: 9639146
references.citation: Blood. 2012 Mar 1;119(9):2171-2
references.pmid: 22383790
references.citation: Clin Cancer Res. 2012 Jun 1;18(11):3163-9
references.pmid: 22496272
references.citation: Lancet Oncol. 2010 Dec;11(12):1149-59
references.pmid: 21094089
references.citation: Life Sci. 2007 Jan 30;80(8):767-74
references.pmid: 17156797
references.citation: J Transl Med. 2009 Aug 23;7:74
references.pmid: 19698176
references.citation: J Ethnopharmacol. 2005 Aug 22;100(1-2):72-9
references.pmid: 16009521
references.citation: Cancer Lett. 2008 Jun 18;264(2):192-200
references.pmid: 18314260
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7
references.pmid: 18040043
references.citation: Clin Cancer Res. 2010 Aug 15;16(16):4217-25
references.pmid: 20601444
references.citation: Nature. 2010 Jan 7;463(7277):103-7
references.pmid: 20023629
references.citation: Leuk Lymphoma. 2007 Nov;48(11):2204-12
references.pmid: 17926190
references.citation: J Nat Prod. 1987 Jan-Feb;50(1):119-31
references.pmid: 3598594
references.citation: Anticancer Res. 1997 Mar-Apr;17(2A):1003-9
references.pmid: 9137441
references.citation: J Thorac Oncol. 2011 Oct;6(10):1757-60
references.pmid: 21918390
references.citation: Biochem Pharmacol. 2003 Jul 1;66(1):93-103
references.pmid: 12818369
references.citation: Arch Biochem Biophys. 2004 Aug 15;428(2):179-87
references.pmid: 15246875
references.citation: Cell Death Differ. 2011 Jan;18(1):60-71
references.pmid: 20577262
references.citation: Blood. 1996 Apr 15;87(8):3069-81
references.pmid: 8605319
references.citation: Blood. 2007 Sep 15;110(6):2057-66
references.pmid: 17536015
references.citation: J Med Chem. 2010 Nov 25;53(22):8000-11
references.pmid: 21033669
references.citation: Blood. 2007 May 15;109(10):4441-9
references.pmid: 17227835
references.citation: Clin Cancer Res. 2012 Jan 15;18(2):487-98
references.pmid: 22128299
references.citation: Blood. 2008 Feb 15;111(4):2300-9
references.pmid: 18056841
references.citation: Lung Cancer. 2011 Dec;74(3):481-5
references.pmid: 21620511
references.citation: Blood. 2007 Jun 15;109(12):5430-8
references.pmid: 17332241
references.citation: Blood. 2008 Mar 15;111(6):3211-9
references.pmid: 18202226
references.citation: J Clin Invest. 2007 Jan;117(1):112-21
references.pmid: 17200714
references.citation: Cell Cycle. 2011 Aug 15;10(16):2792-805
references.pmid: 21822052
references.citation: Leukemia. 2008 Sep;22(9):1712-20
references.pmid: 18596739
references.citation: Mol Cancer. 2008 Feb 14;7:20
references.pmid: 18275607
references.citation: Blood. 2000 Oct 15;96(8):2655-63
references.pmid: 11023495
references.citation: J Biol Chem. 2012 Mar 23;287(13):10224-10235
references.pmid: 22311987
references.citation: Arch Pharm (Weinheim). 2009 Apr;342(4):223-9
references.pmid: 19340835
references.citation: Int J Androl. 1982 Dec;5(6):636-40
references.pmid: 6761275
references.citation: J Clin Oncol. 2011 Mar 1;29(7):909-16
references.pmid: 21282543
references.citation: Cancer Res. 2008 May 1;68(9):3421-8
references.pmid: 18451170
references.citation: Blood. 2012 Jun 14;119(24):5807-16
references.pmid: 22538851
references.citation: J Clin Endocrinol Metab. 1993 Apr;76(4):1019-24
references.pmid: 8473376
references.citation: J Med Chem. 2009 Jul 23;52(14):4511-23
references.pmid: 19555126
references.citation: Br J Haematol. 2008 Jan;140(2):181-90
references.pmid: 18028486
references.citation: Mol Cancer Ther. 2005 Jan;4(1):23-31
references.pmid: 15657350
references.citation: Chem Biol. 2004 Mar;11(3):389-95
references.pmid: 15123268
references.citation: Blood. 2011 Oct 6;118(14):3901-10
references.pmid: 21835956
references.citation: Cancer Chemother Pharmacol. 1992;30(6):480-2
references.pmid: 1394805
references.citation: Clin Exp Pharmacol Physiol. 2004 Oct;31(10):716-22
references.pmid: 15554914
references.citation: Acc Chem Res. 2003 Jun;36(6):417-25
references.pmid: 12809528
references.citation: Blood. 2002 Sep 1;100(5):1795-801
references.pmid: 12176902
references.citation: Anticancer Drugs. 2008 Nov;19(10):967-74
references.pmid: 18827561
references.citation: Leukemia. 2007 Jul;21(7):1549-60
references.pmid: 17460700
references.citation: Cancer Lett. 2009 Jan 8;273(1):107-13
references.pmid: 18782651
references.citation: FASEB J. 2006 Oct;20(12):2147-9
references.pmid: 16935937
references.citation: Mol Pharmacol. 2009 Aug;76(2):327-41
references.pmid: 19483105
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3268-77
references.pmid: 18519752
references.citation: Clin Cancer Res. 2004 Nov 15;10(22):7757-63
references.pmid: 15570010
references.citation: Blood. 2009 Apr 30;113(18):4403-13
references.pmid: 19008458
references.citation: Cell Death Differ. 2009 Jul;16(7):1030-9
references.pmid: 19390557
references.citation: Autophagy. 2010 Oct;6(7):976-8
references.pmid: 20729640
references.citation: J Am Chem Soc. 1971 May 5;93(9):2325-7
references.pmid: 5553076
references.citation: Breast Cancer Res Treat. 2001 Apr;66(3):239-48
references.pmid: 11510695
references.citation: Cancer Cell. 2006 Nov;10(5):375-88
references.pmid: 17097560
references.citation: Semin Oncol. 1997 Apr;24(2):219-40
references.pmid: 9129691
references.citation: Br J Cancer. 1997;76(1):21-8
references.pmid: 9218727
references.citation: Nature. 2011 Mar 3;471(7336):104-9
references.pmid: 21368833
references.citation: Contraception. 2002 Apr;65(4):259-63
references.pmid: 12020773
references.citation: Expert Opin Investig Drugs. 2000 Dec;9(12):2903-11
references.pmid: 11093360
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8785-90
references.pmid: 21555592
references.citation: J Clin Oncol. 2012 Feb 10;30(5):488-96
references.pmid: 22184378
references.citation: Blood. 2009 Jan 8;113(2):299-305
references.pmid: 18931344
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3265-74
references.pmid: 18852130
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):5973-81
references.pmid: 21821698
references.citation: Exp Hematol. 2006 Dec;34(12):1663-9
references.pmid: 17157163
references.citation: Blood. 2008 Oct 1;112(7):2906-16
references.pmid: 18591385
references.citation: Blood. 2009 Jan 1;113(1):149-53
references.pmid: 18836097
references.citation: Oncogene. 2007 Jun 7;26(27):3972-9
references.pmid: 17173063
references.citation: J Med Chem. 2006 Oct 19;49(21):6139-42
references.pmid: 17034116
references.citation: Leukemia. 2009 Nov;23(11):2034-41
references.pmid: 19641525
references.citation: Trends Pharmacol Sci. 1999 May;20(5):196-8
references.pmid: 10354614
references.citation: Tetrahedron Lett. 1970 Mar;(11):815-8
references.pmid: 5436615
references.citation: Cancer Biol Ther. 2008 Sep;7(9):1418-26
references.pmid: 18769131
references.citation: Cell Death Differ. 2008 May;15(5):820-30
references.pmid: 18309326
references.citation: J Cell Physiol. 2012 May;227(5):2145-53
references.pmid: 21780116
references.citation: Cancer. 2012 Feb 15;118(4):1023-31
references.pmid: 21761401
references.citation: J Thorac Oncol. 2011 Apr;6(4):781-5
references.pmid: 21289522
references.citation: Exp Biol Med (Maywood). 2002 Jun;227(6):398-401
references.pmid: 12037129
references.citation: Nat Genet. 1998 Mar;18(3):251-6
references.pmid: 9500547