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´
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˚
Figure 1. X-ray structure (2.4 A resolution) of PTP1Bcomplexed with
19. Color scheme: carbons in orange and green for compound 19,
oxygen in red, nitrogen in blue, and sulfur in yellow.
side chain of the methionine lies on top of a largely
hydrophobic region of the protein, consisted of Met258,
Phe52. The origin of TCPTP selectivity for 19 is not
very clear, since 19 did not interact with any residues
that are different between PTP1Band TCPTP, although
the interaction with Arg24 and Met258 appear to be
critical for achieving such selectivity.
9. Liu, G.; Szczepankiewicz, B. G.; Pei, Z.; Janowick, D.; Xin,
Z.; Liang, H.; Hadjuk, P. J.; Abad-Zapatero, C.; Hutchins, C.
W.; Fesik, S. W.; Ballaron, S. J.; Stashko, M. A.; Lubben, T.;
Mika, A. K.; Zinker, B. A.; Trevillyan, J. M.; Jirousek, M. R.
J. Med. Chem. In press.
10. For in vitro assay protocols, see: Lubben, T.; Clampit, J.;
Stashko, M.; Trevillyan, J.; Jirousek, M.R. In Current Proto-
cols in Pharmacology; Enna, S. J., Williams, M., Ferkany, J.
W., Kenakin, T., Porsolt, R. D., Sullivan, J. P. Eds.; Wiley:
New York, 2001; p 3.8.1.
11. Scherrer, R. A.; Beatty, H. R. J. Org. Chem. 1980, 45,
2127.
12. Skelakatos, G. C.; Paganou, A.; Zervas, L. J. Chem. Soc.
C 1966, 1191.
13. The purity of the compounds tested exceeds 90% as
determined by analytical HPLC.
14. Refined crystallographic coordinates for the structure of
PTP1Bcomplexed with compounds 19 have been deposited
1NZ7.
15. (a) Andersen, H. S.; Olsen, O. H.; Iversen, L. F.; Sor-
ensen, A. L. P.; Mortensen, S. B.; Christensen, M. S.; Branner,
S.; Hansen, T. K.; Lau, J. F.; Jeppesen, L.; Moran, E. J.; Su,
J.; Bakir, F.; Judge, L.; Shahbaz, M.; Collins, T.; Vo, T.;
Newman, M. J.; Ripka, W. C.; Moller, N. P. H. J. Med.
Chem. 2002, 45, 4443. (b) Larsen, S. D.; Barf, T.; Liljebris, C.;
May, P. D.; Ogg, D.; O’Sullivan, T. J.; Palazuk, B. J.; Schos-
tarez, H. J.; Stevens, F. C.; Bleasdale, J. E. J. Med. Chem.
2002, 45, 598.
16. Co-crystalization of TCPTP with inhibitor has failed due
to a multimerization process. See: Iversen, L. F.; Moller, K. B.;
Pedersen, A. K.; Peters, G. H.; Petersen, A. S.; Andersen,
H. S.; Branner, S.; Mortensen, S. B.; Moller, N. P. H. J. Biol.
Chem. 2002, 277, 19982.
In summary, we have discovered the first series of
potent, non-phosphonic acid-containing PTP1Binhibi-
tors with moderate specificity for PTP1Bover TCPTP,
the most homologous phosphatase to PTP1B. We uti-
lized the strategy of occupying both the catalytic site
and the nearby, less homologous, non-catalytic phos-
photyrosyl binding site. This series of PTP1Binhibitors
identified the residues important for achieving TCPTP
specificity in the absence of any structural informa-
tion,16 and provided us with opportunities for designing
more potent and selective PTP1Binhibitors with
improved physical properties.
References and Notes
1. (a) Saltiel, A. R.; Kahn, C. R. Nature 2001, 414, 799. (b)
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Biochem. 2002, 269, 1050.
3. (a) Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish,
W.; Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.;
Himms-Hagen, J.; Chan, C. C.; Ramachandran, C.; Gresser,
M. J.; Tremblay, M. L.; Kennedy, B. P. Science 1999, 283,