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. 2012 Mar 15;20(6):1940-6.
doi: 10.1016/j.bmc.2011.11.004. Epub 2011 Nov 9.

Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors

Yantao He  1 , Li-Fan Zeng, Zhi-Hong Yu, Rongjun He, Sijiu Liu, Zhong-Yin Zhang
Affiliations

Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors

Yantao He et al. Bioorg Med Chem. .

Abstract

Protein tyrosine phosphatases (PTPs) constitute a large and structurally diverse family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. Malfunction of PTP activity has significant implications in many human diseases, and the PTP protein family provides an exciting array of validated diabetes/obesity (PTP1B), oncology (SHP2), autoimmunity (Lyp), and infectious disease (mPTPB) targets. However, despite the fact that PTPs have been garnering attention as novel therapeutic targets, they remain largely an untapped resource. The main challenges facing drug developers by the PTPs are inhibitor specificity and bioavailability. Work over the last ten years has demonstrated that it is feasible to develop potent and selective inhibitors for individual members of the PTP family by tethering together small ligands that can simultaneously occupy both the active site and unique nearby peripheral binding sites. Recent results with the bicyclic salicylic acid pharmacophores indicate that the new chemistry platform may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. Structural analysis of PTP-inhibitor complexes reveals molecular determinants important for the development of more potent and selective PTP inhibitors, thus offering hope in the medicinal chemistry of a largely unexploited protein class with a wealth of attractive drug targets.

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Figures

Figure 1
Figure 1
Intrinsic properties of the PTP active site. A). The active site of PTP (herein PTP1B as an example) is highly conserved, constituted mainly by four loops, generally named as P-loop, WPD-loop, pY-loop and Q-loop. Several residues essential for pTyr binding and catalysis, showing in cyan stick, are highly conserved. B). The active site of PTP is highly positively charged. The electrostatic potential is calculated using APBS1.3 and is mapped onto the molecular surface of PTP1B.
Figure 2
Figure 2
Salicylic acid derivatives as pTyr mimetics.
Figure 3
Figure 3
A strategy for the construction of a benzofuran salicylic acid based focused library using click chemistry.
Figure 4
Figure 4
Structures of I-C11, I-A09, and II-B08.
Figure 5
Figure 5
Crystal structures of Lyp•I-C11 and SHP2•II-B08. Lyp and SHP2 are situated in the same orientation in order to show that although the salicylic cores in I-C11 and II-B08 both occupy the active site, the distal elements in I-C11 and II-B08 interact with different peripheral sites in Lyp and SHP2. A). The structure of Lyp catalytic domain in complex with I-C11. The benzofuran salicylic core occupies the active site whereas the naphthalene ring makes hydrophobic interactions with F28, L29 and R33 locating in the α2′ helix, which includes the unique “Lyp insert” residues. The density for the phenyl group on the bicyclic nucleus is weak in the original structure. Based on its location in I-C11, the phenyl group is not expected to interact with Lyp. The phenyl group depicted in Figure 5A is a model based on its expected position. B). The structure of SHP2 catalytic domain in complex with II-B08. The indole salicylic core also occupies the active site, while the biphenyl group interacts with R362, K364 and K366 locating in the β5–β6-loop.
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