title: SPLINTS: small-molecule protein ligand interface stabilizers.
abstract: Regulatory protein-protein interactions are ubiquitous in biology, and small molecule protein-protein interaction inhibitors are an important focus in drug discovery. Remarkably little attention has been given to the opposite strategy-stabilization of protein-protein interactions, despite the fact that several well-known therapeutics act through this mechanism. From a structural perspective, we consider representative examples of small molecules that induce or stabilize the association of protein domains to inhibit, or alter, signaling for nuclear hormone, GTPase, kinase, phosphatase, and ubiquitin ligase pathways. These SPLINTS (small-molecule protein ligand interface stabilizers) drive interactions that are in some cases physiologically relevant, and in others entirely adventitious. The diverse structural mechanisms employed suggest approaches for a broader and systematic search for such compounds in drug discovery.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: eric_fischer@dfci.harvard.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Fischer
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: eck@crystal.harvard.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. Electronic address: nicolas.thoma@fmi.ch.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Thomä
mesh_terms: D002467:Cell Nucleus / Q000737:chemistry; D020558:GTP Phosphohydrolases / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry; D006728:Hormones / Q000737:chemistry; D008024:Ligands; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D006728:Hormones; D008024:Ligands; D011506:Proteins; D014157:Transcription Factors; D020558:GTP Phosphohydrolases
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