Elsevier

Bioorganic Chemistry

Volume 93, December 2019, 103296
Bioorganic Chemistry

Identification of lipid-like salicylic acid-based derivatives as potent and membrane-permeable PTP1B inhibitors

https://doi.org/10.1016/j.bioorg.2019.103296Get rights and content

Highlights

  • A new series of memebranophilic PTP1B inhibitors was discovered.

  • These inhibitors showed moderate permeability despite their acid-based core.

  • A novel strategy for the optimization of PTP1B inhibitors with better permeability was revealed.

Abstract

Developing protein tyrosine phosphatase-1B (PTP1B) inhibitors is an important strategy to treat type 2 diabetes mellitus (T2DM). Most existing ionic PTP1B inhibitors aren’t of clinical useful due to their low cell-permeability, however. Herein, we introduced a series of lipid-like acid-based (salicylic acid) modules to prepare PTP1B inhibitors, and demonstrated a marked improvement of cell-permeability while maintaining excellent PTP1B inhibitory activity (e.g. compound B12D, IC50 = 0.37 μM against PTP1B and Papp = 1.5 × 10−6 cm/s). We believe that this strategy can be widely utilized to modify potent lead compounds with low cell-permeability.

Introduction

Protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in attenuating insulin sensitivity by dephosphorylating the phosphor-tyrosine residues on the proteins of insulin signal pathway [1]. The PTP1B knockout mice demonstrated increased insulin sensitivity and obesity resistance compared to the wild-type [2]. Additionally, PTP1B inhibition was reported as a potential target for preventing lung metastasis [3] and treating Rett syndrome [4]. Therefore, there is a considerable significance in developing PTP1B inhibitors for associated diseases such as T2DM, obesity, breast cancer, and Rett syndrome [2], [5], [6], [7], [8].

Over the past few decades, numerous structure-based PTP1B inhibitors have been developed [9]. Nevertheless, phosphorylated tyrosine (pTyr) is a charged substrate; thus, typical PTP1B inhibitors (Fig. 1) that fit well into the protein’s active pocket shall carry a charged pharmacophore to achieve adequate PTP1B inhibitory activity. However, the ionic pharmacophore makes these compounds challenging to cross the cell membrane [14], and unsuitable for oral administration.

To solve the membrane permeability issue, lately, many efforts have been made for the identification of new PTP1B inhibitors by applying an uncharged pharmacophore (Fig. 2). Nevertheless, these efforts often led to reduced PTP1B inhibitory activity.

In this study, we demonstrated a novel strategy to produce a group of mono- or bis-anionic amphipathic PTP1B inhibitors by designing and synthesizing a series of lipid-like salicylic acid-based derivatives. The corresponding similarity to the amphiphilic lipids makes these compounds capable of crossing the cell membrane adequately despite the anionic pharmacophore. The acid groups were used to bind to the catalytic site of the protein, and the alkane tails with various lengths were applied to generate further hydrophobic interactions. Thus, we could reveal a rational strategy to provide potent and permeable PTP1B inhibitors. These novel inhibitors could simulate the structure of amphiphilic lipids and demonstrate excellent PTP1B inhibitory activity with sufficient membrane permeability. This study suggests a new scenario for the optimization of potent lead PTP1B inhibitors with low cell permeability.

Section snippets

The lead: The acid-based derivatives with an amphipathic core

Focusing on the cell membranes nature, the compound A16S [19] (Fig. 3), which is originally used as a liposome substance, attracted our attention for its cell membrane crossing abilities. We found out that it also possessed an inhibitory, however weak, activity against PTP1B (IC50 = 174 μM, Papp = 1.7 × 10−6 cm/s) which collectively could make A16S a good option as a lead core in our designing strategy. Docking simulation studies depicted that the salicylic acid group in A16S could bind to the

Discussion

Despite various efforts, such as the molecule charge manipulations and hydrophobicity enhancements for the cell-membrane permeability improvement of PTP1B inhibitors [23], the identification of the potent and bioavailable inhibitors and specifically transforming those into therapeutic applications is still a great challenge. In this research, we introduced a new scenario by simulating the structure of the amphiphilic lipids and created a series of lipid-like anionic molecules. By this strategy,

Acknowledgments

We gratefully acknowledge Dr. Bin Hao, Dr. Xiaohui Wei, and Dr. Pei Cao of Shanghai Jiao Tong University (China) for assistance in PAMPA evaluations.

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