1294
P. Deprez et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1291–1294
major Src SH2 binding pockets are filled similarly, with
a good superposition between the phosphate groups on
one side and the phenyl groups at the bottom of the
hydrophobic pocket on the other side (Fig. 2). As a
consequence, with two carbon less, 21 adopts a ‘short-
cut’ binding mode. However, here again, the seven-
membered ring scaffold appears to be well designed
since it is still lying on the surface generated by the tyr-
osine 61 residue.The structural water molecule (which
was interacting with the lactam ring of 10) is now dis-
placed and replaced directly by the carbonyl of the lac-
tam ring of 21, interacting with the amide nitrogen of
K62. This should be entropically favorable.
5. Charifson, P. S.; Shewchuk, L. M.; Rocque, W.; Hummel,
C. W.; Jordan, S. R.; Mohr, C.; Pacofsky, G. J.; Peel, M. R.;
Rodriguez, M.; Sternbach, D. D.; Consler, T. G. Biochemistry
1997, 36, 6283.
6. (a) Plummer, M. S.; Holland, D. R.; Shahripour, A.; Lun-
ney, E. A.; Fergus, J. H.; Marks, J. S.; McConnel, P.; Mueller,
W. T.; Sawyer, T. K. J. Med. Chem. 1997, 40, 3719. (b) Lun-
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J. H.; Marks, J. S.; Sawyer, T. K. J. Am. Chem. Soc. 1997,
119, 12471. (c) Lunney, E. A.; Para, K. S.; Plummer, M. S.;
Prasad, J. V. N. V.; Saltiel, A. R.; Sawyer, T. K; Shahripour,
A.; Singh, J.; Stankovic, C. J. Patent WO 9712903-A.
7. Beaulieu, P. L.; Cameron, D. R.; Ferland, J.-M.; Gauthier,
J.; Ghiro, E.; Gillard, J.; Gorys, V.; Poirier, M.; Rancourt, J.;
Wernic, D.; Llinas-Brunet, M. J. Med. Chem. 1999, 42, 1757.
8. (a) Buchanan, J. L.; Bohacek, R. S.; Luke, G. P.; Hatada,
M.; Lu, X.; Dalgarno, D. S.; Narula, S. S.; Yuan, R. Y.; Holt,
D. A. Bioorg. Med. Chem. Lett. 1999, 9, 2353. (b) Violette,
S. M.; Shakespeare, W. C.; Bartlett, C.; Guan, W.; Smith,
J. A.; Rickles, R. J.; Bohacek, R. S.; Holt, D. A.; Baron, R.;
Sawyer, T. Chem. Biol. 2000, 7, 225. (c) Shakespeare, W.;
Yang, M.; Bohacek, R.; Cesaroli, F.; Stebbins, K.; Sundar-
amoorthi, R.; Azimioara, M.; Vu, C.; Pradeepan, S.; Metcalf,
C., III; Haraldson, C.; Merry, T.; Dalgarno, D.; Narula, S.;
Hatada, M.; Lu, X.; Van Schravendijk, M. R.; Adams, S.;
Violette, S.; Smith, J.; Guan, W.; Barlett, C.; Herson, J.; Iul-
liucci, J.; Weigele, M.; Sawyer, T. PNAS 2000, 97, 9373.
9. Lesuisse, D.; Deprez, P.; Albert, E.; Duc, T. T.; Sortais, B.;
Gofflo, D.; Jean-Baptiste, V.; Marquette, J.-P.; Schoot, B.;
Sarubbi, E.; Lange, G.; Broto, P.; Mandine, E. Bioorg. Med.
Chem. Lett. 2001, 11, 2127.
However, despite all the positive interactions, benzoic
21 is 300-fold less active than tyrosine 10. One possible
explanation could be that the additional NAc inter-
action present with 10 contributes significantly to the
binding (the carbonyl of Nac interacts with Arg 14). In
this case, the benzoic group is not a potent surrogate of
the tyrosine group for the Src SH2 protein.
In conclusion, we identified compound 10 RU 81843 as
one of the most potent SH2 binder known to date. Its
caprolactam scaffold is able to efficiently deliver the
biphenyl and pY substituents in the respective bind-
ing pockets, whilst also favorably interacting with the
protein.
10. Caprolactam: commercially available (Neosystem);
Thioazepinone: Nobuyoshi, E. FEBS Lett. 1984, 174, 76.
11. Bisarya, S. C.; Roa, R. Synth. Comm. 1992, 22, 3305.
12. (a) Cao, X.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37,
6073. (b) Zhang, C.; Mjalli, A. M. M. Tetrahedron Lett. 1996,
37, 5457.
13. Deprez, P. Tetrahedron Lett. To be submitted.
14. Mc Martin, C.; Bohacek, R. S. J. Comput.-Aided Mol.
Des. 1997, 11, 333.
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