ABSTRACT
Src Homology 2 (SH2) domains are the paradigm of phosphotyrosine (pY) protein recognition modules and mediate numerous cancer-promoting protein-protein complexes. Effective SH2 domain mimicry with pY-binding coordination complexes offers a promising route to new and selective disruptors of pY-mediated protein-protein interactions. We herein report the synthesis and in vitro characterization of a library of coordination complex SH2 domain proteomimetics. Compounds were designed to interact with phosphopeptides via a two-point interaction, principally with pY, and to make secondary interactions with pY+2/3, thereby achieving sequence-selective discrimination. Here, we report that lead mimetics demonstrated high target phosphopeptide affinity (K(a) â¼ 10(7) M(-1)) and selectivity. In addition, biological screening in various tumor cells for anticancer effects showed a high degree of variability in cytotoxicity among receptors, which supported the proposed two-point binding mode. Several receptors potently disrupted cancer cell viability in breast cancer, prostate cancer, and acute myeloid leukemia cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biomimetic Materials/chemical synthesis , Coordination Complexes/chemical synthesis , Phosphopeptides/chemistry , Phosphotyrosine/chemistry , Receptors, Artificial/chemical synthesis , Small Molecule Libraries/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Biomimetic Materials/metabolism , Biomimetic Materials/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/metabolism , Coordination Complexes/pharmacology , Female , High-Throughput Screening Assays , Humans , Kinetics , Male , Models, Molecular , Phosphopeptides/metabolism , Phosphotyrosine/metabolism , Protein Binding , Receptors, Artificial/metabolism , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Spectrometry, Fluorescence , src Homology Domains/geneticsABSTRACT
We report the first application of coordination complexes as functional proteomimetics of the Src homology 2 (SH2) phosphopeptide-binding domain. As a proof-of-concept, functionalized bis-dipicolylamine (BDPA) copper(ii) complexes are shown to disrupt oncogenic Stat3-Stat3 protein complexes and elicit promising anti-tumour activity.
Subject(s)
Coordination Complexes/chemistry , src Homology Domains , Amines/chemistry , Amino Acid Sequence , Animals , Copper/chemistry , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Humans , Mice , NIH 3T3 Cells , Picolinic Acids/chemistry , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , STAT3 Transcription Factor/chemistry , STAT3 Transcription Factor/metabolismABSTRACT
We report the design and synthesis of a novel class of asymmetrically functionalized, ditopic bis-dipicolylamine (BDPA) ligands. A key feature of this research involved the controlled, sequential functional group decoration of a potent molecular recognition scaffold. Calorimetric screening identified a BDPA analogue as a highly potent (K(a) approximately 10(6) M(-1)) and selective sensor for inorganic phosphate.
Subject(s)
Organometallic Compounds/chemistry , Phosphates/analysis , Amines , Anions , Calorimetry , Ligands , Picolinic AcidsABSTRACT
Signal transducer and activator of transcription protein 3 (STAT3) is a latent cytosolic transcription factor that is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutively activated STAT3 protein activity is routinely observed in human cancers, promoting uncontrolled cell proliferation and suppressing apoptosis. Until relatively recently, inhibition of STAT3 transcriptional activity was achieved indirectly via suppression of upstream kinase activators and extracellular cytokine and (or) growth factor stimuli. However, activated STAT3 forms transcriptionally functional STAT3-STAT3 dimers, providing a valid juncture for targeted downstream molecular inhibition. STAT3's prominent role in cancer has seen a decade of innovative and novel approaches to targeting constitutively active STAT3 protein-protein complexes. This mini-review outlines the progress made towards identifying molecular agents capable of silencing aberrant STAT3 signalling through the disruption of STAT3 complexation events.
