4X20

Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications

Summary for 4X20

• Entry DOI: 10.2210/pdb4x20/pdb
• Related: 4X1I 4X1K 4X1Y
• Related PRD ID: PRD_002153
• Descriptor: Tubulin alpha chain, Tubulin beta chain, Stathmin-4, ... (8 entities in total)
• Functional Keywords: binding sites, competitive, cattle, tumor, colchicine, humans, microtubules, protein binding, protein conformation, protein multimerization, tubulin, tubulin modulators, structural protein-inhibitor complex, structural protein/inhibitor
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton : D0VWY9; Golgi apparatus : P63043
• Total number of polymer chains: 5
• Total formula weight: 221276.55

Authors

Parris, K.D. (deposition date: 2014-11-25, release date: 2015-03-25, Last modification date: 2023-09-27)

Primary citation

Maderna, A.,Doroski, M.,Subramanyam, C.,Porte, A.,Leverett, C.A.,Vetelino, B.C.,Chen, Z.,Risley, H.,Parris, K.,Pandit, J.,Varghese, A.H.,Shanker, S.,Song, C.,Sukuru, S.C.,Farley, K.A.,Wagenaar, M.M.,Shapiro, M.J.,Musto, S.,Lam, M.H.,Loganzo, F.,O'Donnell, C.J.
Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.
J.Med.Chem., 57:10527-10543, 2014

PubMed Abstract: Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design.

PubMed: 25431858
DOI: 10.1021/jm501649k

Experimental method

X-RAY DIFFRACTION (3.5 Å)