학술논문
Discovery of Cytotoxic Dolastatin10 Analogues withN-Terminal Modifications.
Document Type
Article
Author
Maderna, Andreas; Doroski, Matthew; Subramanyam, Chakrapani; Porte, Alexander; Leverett, Carolyn A.; Vetelino, Beth C.; Chen, Zecheng; Risley, Hud; Parris, Kevin; Pandit, Jayvardhan; Varghese, Alison H.; Shanker, Suman; Song, Cynthia; Sukuru, Sai Chetan K.; Farley, Kathleen A.; Wagenaar, Melissa M.; Shapiro, Michael J.; Musto, Sylvia; Lam, My-Hanh; Loganzo, Frank
Source
Subject
*ANTINEOPLASTIC agents
*DOLASTATIN
*CRYSTAL structure
*PEPTIDES
*CHEMICAL sample preparation
*MICROTUBULES
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Language
ISSN
0022-2623
Abstract
Auristatins,synthetic analogues of the antineoplastic naturalproduct Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitorsthat are clinically used as payloads in antibody–drug conjugates(ADCs). The design and synthesis of several new auristatin analogueswith N-terminal modifications that include amino acids with α,α-disubstitutedcarbon atoms are described, including the discovery of our lead auristatin,PF-06380101. This modification of the peptide structure is unprecedentedand led to analogues with excellent potencies in tumor cell proliferationassays and differential ADME properties when compared to other syntheticauristatin analogues that are used in the preparation of ADCs. Inaddition, auristatin cocrystal structures with tubulin are being presentedthat allow for the detailed examination of their binding modes. Asurprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevanttubulin bound state, whereas in solution this bond is exclusivelyin the trans-configuration. This remarkable observationshines light onto the preferred binding mode of auristatins and servesas a valuable tool for structure-based drug design. [ABSTRACT FROM AUTHOR]