Therapeutic use of PDZ protein-protein interaction antagonism.
PDZ domains are important interaction modules in many intracellular pathways and abnormal activations of many of those pathways lead to diseases, including several types of cancer. The domains are characterized by the ability to recognize the extreme COOH-terminus of target proteins, such as G protein-coupled receptors and ion channels. Because PDZ protein-protein interaction is a key factor in the function of cellular pathways and signal transmission in those pathways, developing small-molecule inhibitors to compete with PDZ targets is very attractive in dissecting molecular mechanisms and formulating pharmaceutical agents. Moreover, there is a growing interest in developing small-molecule drugs to block signaling within cells. The modulation of PDZ-involved interactions in cells might be an approach to target the G protein-coupled receptors and ion channels, which are among the most important classes of drug targets in the pharmaceutical industry today. Here, we review recent progress in the development of small-molecule PDZ inhibitors, and especially focus on two PDZ domain-containing target proteins, postsynaptic density 95 and dishevelled.
Wang
Nick X
NX
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Lee
Ho-Jin
HJ
Zheng
Jie J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D054731:PDZ Domains / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D000970:Antineoplastic Agents; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D052248:Nitric Oxide Synthase Type I