Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies.
To facilitate the discovery of clinically useful Stat3 inhibitors, computational analysis of the binding to Stat3 of the existing Stat3 dimerization disruptors and quantitative structure-activity relationships (QSAR) were pursued, by which a pharmacophore model was derived for predicting optimized Stat3 dimerization inhibitors. The 2,6,9-trisubstituted-purine scaffold was functionalized in order to access the three subpockets of the Stat3 SH2 domain surface and to derive potent Stat3-binding inhibitors. Select purine scaffolds showed good affinities (K(D), 0.8-12 μM) for purified, nonphosphorylated Stat3 and inhibited Stat3 DNA-binding activity in vitro and intracellular phosphorylation at 20-60 μM. Furthermore, agents selectively suppressed viability of human prostate, breast and pancreatic cancer cells, and v-Src-transformed mouse fibroblasts that harbor aberrant Stat3 activity. Studies herein identified novel small-molecule trisubstituted purines as effective inhibitors of constitutively active Stat3 and of the viability of Stat3-dependent tumor cells, and are the first to validate the use of purine bases as templates for building novel Stat3 inhibitors.
Vijay M
VM
Shahani
Peibin
P
Yue
Sina
S
Haftchenary
Wei
W
Zhao
Julie L
JL
Lukkarila
Xiaolei
X
Zhang
Daniel
D
Ball
Christina
C
Nona
Patrick T
PT
Gunning
James
J
Turkson
Expert Opin Ther Targets. 2004 Oct;8(5):409-22
15469392
Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4700-5
15781862
J Med Chem. 2009 Apr 23;52(8):2429-42
19334714
Expert Opin Investig Drugs. 2009 Jan;18(1):45-56
19053881
Chembiochem. 2008 Nov 24;9(17):2800-3
19006150
J Med Chem. 2005 Oct 20;48(21):6661-70
16220982
Cancer Res. 2010 Mar 15;70(6):2445-54
20215512
Adv Exp Med Biol. 2009;611:545-6
19400306
Mol Cancer Ther. 2004 Mar;3(3):261-9
15026546
Nature. 1998 Jul 9;394(6689):145-51
9671298
J Mol Biol. 1997 Apr 4;267(3):727-48
9126849
J Biol Chem. 2001 Nov 30;276(48):45443-55
11579100
Mol Cancer Ther. 2004 Dec;3(12):1533-42
15634646
Bioorg Med Chem Lett. 2008 Jan 1;18(1):391-5
18006313
J Biol Chem. 2005 Sep 23;280(38):32979-88
16046414
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
17463090
Nat Rev Cancer. 2002 Oct;2(10):740-9
12360277
Lancet Oncol. 2002 Jul;3(7):415-24
12142171
ACS Med Chem Lett. 2010 May 13;1(2):85-89
20596242
ACS Chem Biol. 2007 Dec 21;2(12):787-98
18154266
Curr Opin Investig Drugs. 2004 Jun;5(6):592-6
15242246
Bioorg Med Chem Lett. 2007 Apr 1;17(7):1875-8
17336521
ChemMedChem. 2008 Aug;3(8):1159-68
18683176
Chem Biol. 2006 Nov;13(11):1235-42
17114005
Bioorg Med Chem Lett. 2003 Feb 24;13(4):633-6
12639546
Biochem Pharmacol. 2010 May 15;79(10):1398-409
20067773
Oncogene. 2000 Dec 27;19(56):6613-26
11426647