A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.
The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.
Cerchietti
Leandro C
LC
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Ghetu
Alexandru F
AF
Zhu
Xiao
X
Da Silva
Gustavo F
GF
Zhong
Shijun
S
Matthews
Marilyn
M
Bunting
Karen L
KL
Polo
Jose M
JM
Farès
Christophe
C
Arrowsmith
Cheryl H
CH
Yang
Shao Ning
SN
Garcia
Monica
M
Coop
Andrew
A
Mackerell
Alexander D
AD
Privé
Gilbert G
GG
Melnick
Ari
A
D000818:Animals; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D014158:Transcription, Genetic; D016335:Zinc Fingers
C411984:BCOR protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins
Nature. 2007 Dec 13;450(7172):1001-9
18075579
Cell. 2004 Oct 1;119(1):75-86
15454082
Genome Biol. 2005;6(10):R82
16207353
J Biomol Screen. 2006 Feb;11(1):5-12
16234338
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Curr Top Med Chem. 2007;7(1):63-82
17266596
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
J Antimicrob Chemother. 2009 Nov;64(5):1035-43
19759040
Mol Cell Biol. 2008 Apr;28(7):2175-86
18212045
Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14198-203
15375218
Cell. 2007 Jan 26;128(2):257-67
17254965
J Med Chem. 2005 Jul 14;48(14):4586-95
15999996
J Pharmacol Exp Ther. 2000 Jun;293(3):761-70
10869374
Cancer Cell. 2005 May;7(5):445-55
15894265
Blood. 2007 Sep 15;110(6):2067-74
17545502
Nat Med. 2004 Dec;10(12):1329-35
15531890
Antimicrob Agents Chemother. 1993 Nov;37(11):2318-22
8285612
Blood Cells Mol Dis. 2008 Jul-Aug;41(1):95-9
18346918
Nature. 2004 Dec 2;432(7017):635-9
15577913
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3207-12
17360630
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
Mol Interv. 2001 Apr;1(1):40-53
14993337
Cancer Invest. 2000;18(4):356-65
10808372
J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
11274893
Science. 1992 Aug 21;257(5073):1078-82
1509259
Cancer Res. 2008 May 1;68(9):3361-9
18451163
Acta Crystallogr D Biol Crystallogr. 2006 Aug;62(Pt 8):859-66
16855301
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
Curr Opin Chem Biol. 2004 Aug;8(4):442-9
15288255
Mol Cell. 2003 Dec;12(6):1551-64
14690607
Protein Sci. 2007 Feb;16(2):336-42
17189472
Nat Chem Biol. 2009 May;5(5):358-64
19305397
Nat Immunol. 2005 Oct;6(10):1054-60
16142238
Science. 1997 Apr 25;276(5312):589-92
9110977
Blood. 2009 Apr 9;113(15):3397-405
18927431
J Med Chem. 2004 Oct 7;47(21):5085-93
15456252
Antimicrob Agents Chemother. 1994 Feb;38(2):217-22
8192446
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
19461840
J Med Chem. 2004 Jul 1;47(14):3502-11
15214778
J Mol Biol. 1982 Oct 25;161(2):269-88
7154081
J Nucl Med. 2005 Nov;46(11):1835-41
16269597
J Med Chem. 2002 May 23;45(11):2213-21
12014959
Nat Immunol. 2007 Jul;8(7):705-14
17558410
Mol Cell. 2008 Feb 15;29(3):384-91
18280243
J Comput Aided Mol Des. 2001 May;15(5):411-28
11394736
Cell Cycle. 2005 Feb;4(2):239-41
15655367
J Chem Inf Comput Sci. 2003 Jan-Feb;43(1):267-72
12546562
J Chem Inf Model. 2005 Nov-Dec;45(6):1812-9
16309288
Nat Genet. 1997 Jun;16(2):161-70
9171827