Abstract
Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs. In this review, we summarize recent developments in successful targeting of IDPs, all of which are involved in different cancer types. The strategies used to develop and design (or in one particular example, to repurpose) small molecules targeting IDPs are, in a global sense, similar to those used in well-folded proteins: (1) screening of chemically diverse or target-oriented compound libraries; or (2) study of the interfaces involved in recognition of their natural partners, and design of molecular candidates capable of binding to such binding interface. We describe the outcomes of using these approaches in targeting IDPs involved in cancer, in the view to providing insight, to target IDPs in general. In a broad sense, the designed small molecules seem to target the most hydrophobic regions of the IDPs, hampering macromolecule (DNA or protein)–IDP interactions; furthermore, in most of the molecule–IDP complexes described so far, the protein remains disordered.
Highlights
circular dichroism (CD) Circular dichroism cdk Cyclin-dependent kinase C-PTP1B Disordered C-terminal region of protein tyrosine phosphatase 1B EFP Ewing’s fusion protein EWS Ewing’s sarcoma oncoprotein fluorescence resonance energy transfer (FRET) Fluorescence resonance energy transfer HER2 Human epidermal growth factor receptor 2 intrinsically disordered (ID) Intrinsically disordered Intrinsically disordered proteins (IDPs) Intrinsically disordered protein isothermal titration calorimetry (ITC) Isothermal titration calorimetry KID Kinase inhibitory domain lactate dehydrogenase (LDH) Lactate dehydrogenase MD Molecular dynamics MDM2 Murine double minute 2 Mixed Lineage Leukemia (MLL) Mixed lineage leukemia NMR Nuclear magnetic resonance NUPR1 Nuclear protein 1 p53-transcriptional activation domain (TA) The TA of p53, comprising residues 1–61 of the whole intact p53 protein pancreatic adenocarcinoma (PDAC) Pancreatic ductal adenocarcinoma PP Protein–protein protein–protein interactions (PPIs) Protein–protein interaction PTP1B Protein tyrosine phosphatase 1B reactive oxygen species (ROS) Reactive oxygen species small angle X-ray scattering (SAXS) Small-angle X-ray scattering size exclusion chromatography (SEC) Size-exclusion chromatography surface plasmon resonance (SPR) Surface plasmon resonance TA Transcriptional activation domain transcription factor (TF) Transcription factor TFP Trifluoperazine twoyeast hybrid (TYH) Two-yeast hybrid
Our work and examples from other laboratories indicate that targeting of IDPs is feasible
In all cases described so far, the molecules work by hampering the DNA–protein or protein–protein interactions in which the IDP is implicated
Summary
The oncogenic transcription factor (TF) c-Myc is involved in cell growth, apoptosis, and metabolic processes [15, 16]. MSI-1436 disrupts HER2 signaling and inhibits tumorigenesis in xenografted mice, showing that PTP1B is, as well, a valid target to treat breast cancer [36] In this example, the targeting of the disordered protein with small molecules does not hamper directly the interaction with other proteins (as in the case of c-Myc/ Max system), but rather induces allosteric conformational changes, which impedes subsequent binding (and its biological function). This structure has been used as a starting point to develop inhibitory compounds applying the two approaches used for targeting IDPs: (1) the design of a peptide or peptide mimetic with the features of the p53-TA region; and (2) screening of libraries of compounds that could fit into the hydrophobic groove of MDM2 Both approaches have allowed the screening, design, synthesis and testing (using fluorescence, CD, NMR, and SPR) of several dozens of small inhibitors of this PPI interface [70–72], and even the design of peptides and peptide mimetics which have an affinity similar to that of both intact protein partners [73]. The compound, obtained by rational ligand-based design, binds to the hydrophobic regions of NUPR1 as in other IDPs and forms a fuzzy complex with the protein
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