 |
PDBsum entry 4x1k
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Structural protein/inhibitor
|
PDB id
|
|
|
|
4x1k
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
429 a.a.
|
|
|
|
|
|
|
|
|
|
|
428 a.a.
|
|
|
|
|
|
|
|
|
|
|
123 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Discovery of cytotoxic dolastatin 10 analogues with n-Terminal modifications.
|
|
|
Authors
|
|
A.Maderna,
M.Doroski,
C.Subramanyam,
A.Porte,
C.A.Leverett,
B.C.Vetelino,
Z.Chen,
H.Risley,
K.Parris,
J.Pandit,
A.H.Varghese,
S.Shanker,
C.Song,
S.C.Sukuru,
K.A.Farley,
M.M.Wagenaar,
M.J.Shapiro,
S.Musto,
M.H.Lam,
F.Loganzo,
C.J.O'Donnell.
|
|
|
Ref.
|
|
J Med Chem, 2014,
57,
10527-10543.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
