Inhibition of Low Molecular Weight Protein Tyrosine Phosphatase by an Induced-Fit Mechanism.
The low molecular weight protein tyrosine phosphatase (LMW-PTP) is a regulator of a number of signaling pathways and has been implicated as a potential target for oncology and diabetes/obesity. There is significant therapeutic interest in developing potent and selective inhibitors to control LMW-PTP activity. We report the discovery of a novel class of LMW-PTP inhibitors derived from sulfophenyl acetic amide (SPAA), some of which exhibit greater than 50-fold preference for LMW-PTP over a large panel of PTPs. X-ray crystallography reveals that binding of SPAA-based inhibitors induces a striking conformational change in the LMW-PTP active site, leading to the formation of a previously undisclosed hydrophobic pocket to accommodate the α-phenyl ring in the ligand. This induced-fit mechanism is likely a major contributor responsible for the exquisite inhibitor selectivity.
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Rongjun
R
He
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Jifeng
J
Wang
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Zhi-Hong
ZH
Yu
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Ruo-Yu
RY
Zhang
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Sijiu
S
Liu
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Li
L
Wu
Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
Zhong-Yin
ZY
Zhang
Biochemistry. 2000 Feb 29;39(8):1903-14
10684639
Biochem Biophys Res Commun. 2000 Apr 13;270(2):564-9
10753664
Biochem Biophys Res Commun. 2001 Nov 30;289(2):602-7
11716518
Mol Cell Biol. 2002 May;22(10):3404-14
11971972
J Biol Chem. 2002 Oct 4;277(40):37331-8
12149261
J Biol Chem. 2002 Oct 18;277(42):39274-9
12167657
Mol Genet Metab. 2002 Nov;77(3):226-9
12409270
J Cell Biol. 2003 Jun 9;161(5):933-44
12796479
Biochem Biophys Res Commun. 2003 Dec 12;312(2):360-6
14637146
Bioorg Med Chem. 2004 Apr 15;12(8):1867-80
15051056
Cell. 2004 Jun 11;117(6):699-711
15186772
Metabolism. 2005 Jul;54(7):891-4
15988697
Biochem Biophys Res Commun. 2005 Sep 2;334(3):875-83
16036221
Protein Sci. 2006 Oct;15(10):2381-94
17008719
J Biol Chem. 2007 May 11;282(19):14291-9
17353188
Eur J Med Chem. 2007 Aug;42(8):1102-8
17367895
Int J Cancer. 2008 Apr 1;122(7):1675-8
18058797
Biochemistry. 2008 Feb 12;47(6):1482-9
18197699
Bioorg Med Chem. 2009 Mar 1;17(5):1928-37
19217304
Curr Opin Cell Biol. 2009 Apr;21(2):140-6
19269802
ChemMedChem. 2009 Jun;4(6):957-62
19288492
Bioorg Med Chem. 2009 Apr 1;17(7):2658-72
19297174
Acta Diabetol. 2010 Dec;47 Suppl 1:139-43
19855922
Bioorg Med Chem. 2010 Jul 15;18(14):5449-56
20538467
Proc Natl Acad Sci U S A. 2011 May 24;108(21):8803-8
21555563
Arch Biochem Biophys. 1990 Oct;282(1):39-49
2171433
J Med Chem. 2012 Jan 12;55(1):2-22
21988196
Eur J Med Chem. 2012 Apr;50:332-43
22381357
Acc Chem Res. 2013 Apr 16;46(4):927-36
22872015
ACS Chem Biol. 2013 Jan 18;8(1):96-104
23276252
Bioorg Med Chem Lett. 2013 Nov 1;23(21):5912-4
24035092
Acta Pharmacol Sin. 2014 Oct;35(10):1227-46
25220640
Oncotarget. 2015 Apr 10;6(10):8300-12
25811796
Eur Urol. 2016 Apr;69(4):710-719
26159288
ACS Med Chem Lett. 2015 Jun 08;6(7):782-6
26191366
FEBS Lett. 1989 Jul 3;250(2):469-73
2787757
FEBS Lett. 1986 Jul 28;203(2):139-43
3089835
Science. 1985 Jul 5;229(4708):23-8
3892686
Biochem Biophys Res Commun. 1997 Sep 18;238(2):676-82
9299573
Genes Dev. 1998 Mar 1;12(5):667-78
9499402
J Biol Chem. 1998 Jun 19;273(25):15458-63
9624131
J Biol Chem. 1998 Aug 21;273(34):21714-20
9705307