4X1I: Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications

Citation:
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 alpha,alpha-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.
PDB ID: 4X1IDownload
MMDB ID: 128113
PDB Deposition Date: 2014/11/24
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 3.11  Å
Source Organism:
Ovis aries
Similar Structures:
Biological Unit for 4X1I: pentameric; determined by author and by software (PISA)
Molecular Components in 4X1I
Label Count Molecule
Proteins (5 molecules)
2
Tubulin Alpha Chain
Molecule annotation
2
Tubulin Beta Chain
Molecule annotation
1
Stathmin-4(Gene symbol: Stmn4)
Molecule annotation
Chemicals (10 molecules)
1
2
2
2
3
2
4
2
5
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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