Developing Antagonists for the Met-HGF/SF Protein-Protein Interaction Using a Fragment-Based Approach was written by Winter, Anja;Sigurdardottir, Anna G.;DiCara, Danielle;Valenti, Giovanni;Blundell, Tom L.;Gherardi, Ermanno. And the article was included in Molecular Cancer Therapeutics in 2016.Electric Literature of C12H17NO This article mentions the following:
In many cancers, aberrant activation of the Met receptor tyrosine kinase leads to dissociation of cells from the primary tumor, causing metastasis. Accordingly, Met is a high-profile target for the development of cancer therapies, and progress has been made through development of small mol. kinase inhibitors and antibodies. However, both approaches pose significant challenges with respect to either target specificity (kinase inhibitors) or the cost involved in treating large patient cohorts (antibodies). Here, we use a fragment-based approach in order to target the protein-protein interaction (PPI) between the α-chain of hepatocyte growth factor/scatter factor (HGF/SF; the NK1 fragment) and its high-affinity binding site located on the Met Sema domain. Surface plasmon resonance was used for initial fragment library screening and hits were developed into larger compounds using substructure (similarity) searches. We identified compounds able to interfere with NK1 binding to Met, disrupt Met signaling, and inhibit tumorsphere generation and cell migration. Using mol. docking, we concluded that some of these compounds inhibit the PPI directly, whereas others act indirectly. Our results indicate that chem. fragments can efficiently target the HGF/SF-Met interface and may be used as building blocks for generating biol. active lead compounds This strategy may have broad application for the development of a new class of Met inhibitors, namely receptor antagonists, and in general for the development of small mol. PPI inhibitors of key therapeutic targets when structural information is not available. Mol Cancer Ther; 15(1); 3-14. ©2015 AACR. In the experiment, the researchers used many compounds, for example, 4-(2-Methoxyphenyl)piperidine (cas: 58333-75-8Electric Literature of C12H17NO).
4-(2-Methoxyphenyl)piperidine (cas: 58333-75-8) belongs to piperidine derivatives. The piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste. Some chemotherapeutic agents have piperidine moiety within their structure, foremost among them, vinblastine and raloxifene.Electric Literature of C12H17NO
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem