Bidentate PTP Inhibitors

Although pTyr is essential for peptide/protein substrate recognition, pTyr alone does not possess high affinity for PTPs [45]. This and the fact that the PTP active site (pTyr binding site) is highly conserved among various PTPs present a serious challenge for the development of potent and selective PTP inhibitors targeted primarily to the active site. The discovery of a second aryl phosphate-binding site in PTP1B (defined by residues Arg24, Arg254, Met258, Gly259, and Gln262), which is not conserved among the PTPs and is adjacent to the active site, provides a novel paradigm for the design of tight-binding and specific PTP1B inhibitors that can span both sites [30]. Moreover, kinetic and structural studies have shown that amino acid residues flanking the pTyr are also required for efficient PTP substrate recognition [29,45-48]. These results suggest that subpockets adjacent to the PTP active site may also be targeted for inhibitor development. Consequently, an effective strategy for PTP inhibitor design is to attach a nonhydrolyzable pTyr surrogate to a properly functionalized structural element, which interacts with the immediate surroundings beyond the catalytic site. This strategy produces bidentate PTP inhibitors that simultaneously bind both the active site and a unique adjacent peripheral site, thereby exhibiting both enhanced affinity and specificity.

Figure 2 Structures of nonhydrolyzable pTyr surrogates.

Initial attempts to exploit this strategy generated several to-aryldifluorophosphonate inhibitors that display modest selectivity for PTP1B [40,49,50]. Recent medicinal chemistry efforts directed to optimization of the 3-carboxy-4-(O-carboxymethyl) tyrosine core (Fig. 2, compound 13) and its attached peptide template led to several small molecule pep-tidomimetics (e.g., compounds 21 and 22 in Fig. 3) that displayed sub- to micromolar potency against PTP1B and augmented insulin action in the cell [51,52]. Using a structure-based approach, the Novo Nordisk group was able to introduce a substituent into the core structure of 2-(oxalylamino)-benzoic acid (Fig. 2, compound 18) to address the second aryl phosphate-binding pocket in PTP1B [53]. This transformed a general, low-affinity, and nonselective PTP inhibitor into a reasonably potent (K=0.6 |M) and selective inhibitor for PTP1B (Fig. 3, compound 23). A completely different approach (namely, combinatorial chemistry) was employed to identify bidentate PTP1B inhibitors capable of simultaneously occupying both the active site and a unique peripheral site in PTP1B [54]. This effort resulted in the identification of compound 24 in Fig. 3, which displays a K value of 2.4 nM for PTP1B and exhibits several orders of magnitude selectivity in favor of PTP1B against a panel of PTPs. Compound 24 is the most potent and selective PTP1B inhibitor identified to date. Subsequent structural and mutagenesis studies reveal that the distal element in compound 24 does not interact with the second aryl phosphate-binding pocket, but rather occupies a distinct area involving residues Lys41, Asn44, Tyr46, Arg47, Asp48, Lys116, and Phe182 [62]. The interactions between compound 24 and PTP1B are unique and provide the molecular basis for its potency and selectivity for PTP1B. Collectively, these results demonstrate that it is feasible to acquire potent, yet highly selective, PTP inhibitory agents.

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