Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6547
(4) Tonks, N. K.; Diltz, C. D.; Fischer, E. H. Purification of the major
protein-tyrosine-phosphatases of human placenta. J. Biol. Chem.
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S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.;
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L.; Kennedy, B. P. Increased insulin sensitivity and obesity
resistance in mice lacking the protein tyrosine phosphatase-1b
gene. Science 1999, 283, 1544-1548.
(6) Klaman, L. D.; Boss, O.; Peroni, O. D.; Kim, J. K.; Martino, J.
L.; Zabolotny, J. M.; Moghal, N.; Lubkin, M.; Kim, Y. B.; Sharpe,
A. H.; Stricker-Krongrad, A.; Shulman, G. I.; Neel, B. G.; Kahn,
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tissue-specific insulin sensitivity in protein-tyrosine phosphatase
1b-deficient mice. Mol. Cell. Biol. 2000, 20, 5479-5489.
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oligonucleotide lowers ptp1b protein, normalizes blood glucose,
and improves insulin sensitivity in diabetic mice. Proc. Natl.
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M. L.; Wang, X.-Y.; Thompson, D. P.; Conradi, R. A.; Mathews,
W. R.; Laborde, A. L.; Stuchly, C. W.; Heijbel, A.; Bergdahl, K.;
Bannow, C. A.; Smith, C. W.; Svensson, C.; Liljebris, C.;
Schostarez, H. J.; May, P. D.; Stevens, F. C.; Larsen, S. D. Small
molecule peptidomimetics containing a novel phosphotyrosine
bioisostere inhibit protein tyrosine phosphatase 1b and augment
insulin action. Biochemistry 2001, 40, 5642-5654.
Figure 5. Crystal structure of PTP1B/12 showing the (S)-
IZD heterocyclic pTyr mimetic VIII bound to the phosphate
binding loop of PTP1B. The protein is depicted in ribbon-and-
stick style, and the inhibitor is depicted in ball-and-stick style.
The (S)-IZD heterocycle makes all of the predicted polar
contacts and displaces all three active site water molecules.
Hydrogen bonds are indicated with dashed lines.
heterocycle binds at the center of the phosphate binding
loop (Cys215-Arg221), where each of the three oxygen
atoms of the (S)-IZD heterocycle displaces a structural
water molecule and forms the expected hydrogen-
bonding interactions with backbone amides and side
chain of Arg221. The aryl ring directly attached to the
(S)-IZD heterocycle participates in extensive van der
Waals interactions with Tyr46, Val49, Ile219, and F182
of the flap. The peptidic portion of 12 binds in an ex-
tended conformation, identical to other known peptide-
like structures bound to PTP1B (see Supporting Infor-
mation for full view of inhibitor 12 bound to PTP1B).
Novel heterocyclic pTyr mimetics were designed
through meticulous analysis and overlay of structural
information available in the PDB. A dipeptide contain-
ing the (S)-IZD pTyr mimetic was synthesized and
demonstrated competitive, reversible, and potent inhibi-
tion of PTP1B (12, Ki ) 180 nM). An X-ray crystal
structure of PTP1B/12 showed that the ligand bound
precisely as designed in silico. Furthermore, the (S)-IZD
pTyr mimetic was found to be a 10-fold more potent
inhibitor of PTP1B than an analogous peptidic com-
pound bearing a DFMP. These data support the conclu-
sion that the (S)-IZD heterocycle is the most potent pTyr
mimetic discovered to date. While the peptidic inhibitors
described herein are not cell-permeable or orally bio-
available, these diffusely anionic IZD heterocyclic pTyr
mimetics provide new opportunities for the discovery
of such PTP1B inhibitors when incorporated into suit-
able nonpeptidic scaffolds.
(9) McGovern, S. L.; Caselli, E.; Grigorieff, N.; Shoichet, B. K. A
common mechanism underlying promiscuous inhibitors from
virtual and high-throughput screening. J. Med. Chem. 2002, 45,
1712-1722.
(10) Burke, T. R., Jr.; Lee, K. Phosphotyrosyl mimetics in the
development of signal transduction inhibitors. Acc. Chem. Res.
2003, 36, 426-433.
(11) Pannifer, A. D. B.; Flint, A. J.; Tonks, N. K.; Barford, D.
Visualization of the cysteinyl-phosphate intermediate of
a
protein-tyrosine phosphatase by X-ray crystallography. J. Biol.
Chem. 1998, 273, 10454-10462.
(12) Combs, A. P.; Yue, E. W. T.; Bower, M. J.; Zhu, W.; Crawley, M.
L.; Sparks, R. B.; Pruitt, J. R.; Takvorian, A. Inhibitors of
proteins that bind phosphorylated molecules. PCT Int. Appl. WO
2005035551, 2005; p 529 (Incyte Corporation).
(13) Dunitz, J. D. The entropic cost of bound water in crystals and
biomolecules. Science 1994, 264, 670.
(14) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.;
Ru, Y.; Bacheler, L. T.; Meek, O. M. J.; Rayner, M. M. Rational
design of potent, bioavailable, nonpeptide cyclic ureas as HIV
protease inhibitors. Science 1994, 263, 380-384.
(15) At the time of our research, compounds containing the TDZ
heterocycle were not published in any patent or journal articles.
The following patents and papers in references 15-19 have since
been published. Coppola, G. M.; Davies, J. W.; Jewell, C. F., Jr.;
Li, Y.-C.; Wareing, J. R.; Sperbeck, D. M.; Stams, T. M.; Topiol,
S. W.; Vlattas, I. Preparation of substituted 1,1-dioxo-1,2,5-
thiazolidine-3-ones as protein tyrosine phosphatase 1b and t-cell
protein tyrosine phosphatase inhibitors to mitigate insulin
resistance in the treatment of diabetes or atherosclerosis. PCT
Int. Appl. WO 2003:796679, 2003;
p 148 (Novartis A.-G.,
Switzerland; Novartis Pharma G.m.b.H.).
(16) Kenny, P. W.; Morley, A. D.; Russell, D. J.; Toader, D. Prepara-
tion of 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives as
inhibitors of protein tyrosine phosphatase 1b. PCT Int. Appl.
WO 2004050646, 2004; p 48 (Astrazeneca AB, Sweden; Astra-
zeneca U.K. Ltd.).
(17) Birch, A. M.; Kenny, P. W.; Morley, A. D.; Russell, D. J.; Toader,
D. Preparation of 5-(substituted phenyl)thiadiazolidin-3-ones as
inhibitors of protein tyrosine phosphatase 1b. PCT Int. Appl.
WO 2004:412929, 2004; p 89 (Astrazeneca AB, Sweden; Astra-
zeneca U.K. Ltd.).
(18) Saunders, J. O.; Miknis, G. F.; Blake, J. F. Preparation of
sulfahydantoins as phosphate isosteres for use as phosphatase
inhibitors in the treatment of cancer and autoimmune disorders.
PCT Int. Appl. WO 2004062664, 2004; p 62 (Vertex Pharma-
ceuticals Incorporated).
(19) Black, E.; Breed, J.; Breeze, A. L.; Embrey, K.; Garcia, R.; Gero,
T. W.; Godfrey, L.; Kenny, P. W.; Morley, A. D.; Minshull, C. A.
Structure-based design of protein tyrosine phosphatase-1b in-
hibitors. Bioorg. Med. Chem. Lett. 2005, 15, 2503-2507.
(20) Uehling, D. E.; Donaldson, K. H.; Deaton, D. N.; Hyman, C. E.;
Sugg, E. E.; Barrett, D. G.; Hughes, R. G.; Reitter, B.; Adkison,
K. K.; Lancaster, M. E.; Lee, F.; Hart, R.; Paulik, M. A.;
Acknowledgment. We thank Rakesh Kohli at the
University of Pennsylvania for providing HRMS data.
Supporting Information Available: Synthesis proce-
dures and analytical data for intermediates and final products
(1H NMR, 13C NMR, HRMS, HPLC), experimental procedures
for the biological assays, ab initio modeling, and crystal-
lographic methods and data. This material is available free of
References
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