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The Challenge of Drugging Undruggable Targets in Cancer: Lessons Learned from Targeting BCL-2 Family Members

Authors' Affiliations: ¹ Department of Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, ² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, and ³ Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Gregory L. Verdine, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138. Phone: 617-495-5323; Fax: 617-495-8755; E-mail: gregory_verdine{at}harvard.edu.

Abstract

The genomic and proteomic revolutions have provided us with an ever-increasing number of mechanistic insights into cancer pathogenesis. Mutated genes and pathologic protein products have emerged as the basis for modern anticancer drug development. With the increasing realization of the importance of disrupting oncogenic protein-protein interaction, new challenges have emerged for classical small molecule and protein-based drug modalities, i.e., the critical need to target flat and extended protein surfaces. Here, we highlight two distinct technologies that are being used to bridge the pharmacologic gap between small molecules and protein therapeutics. With the BCL-2 family of survival proteins as their substrate for intracellular targeting, we conclude that peptide stapling and fragment-based drug discovery show promise to traverse the critical surface features of proteins that drive human cancer.

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