Inhibiting Interactions

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Science  07 Aug 2009:
Vol. 325, Issue 5941, pp. 657
DOI: 10.1126/science.325_657b

Although the genetic bases of many cancers have been identified, there remains the challenge of translating this knowledge into promising drug candidates. The discovery of the chromosomal translocation that fuses the BCR and Abl genes and leads to the development of chronic myeloid leukemia was followed by spectacular clinical data attesting the efficacy of the inhibitor imatinib mesylate in the late 1990s. Ewing's sarcoma family tumors are also caused by a chromosomal translocation, most commonly one that fuses the EWS and FLI1 genes. The resulting EWS-FLI1 transcription factor both lacks enzymatic activity and is inherently disordered, making it difficult to screen chemical libraries for inhibitors. EWS-FLI1 does, however, bind to RNA helicase A, which acts as a transcriptional coactivator, and this interaction is important for tumorigenesis. Erkizan et al. designed a peptide to inhibit binding and used it to identify a small molecule (YK-4-279) that specifically blocked EWS-FLI1 binding to RNA helicase A and also decreased tumor growth in mouse xenograft assays. This strategy may be valuable for developing lead molecules in other cancers caused by similar types of fusion proteins.

Nature Med. 15, 750 (2009).

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