 |
PDBsum entry 6c8c
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
A small molecule targeting mutagenic translesion synthesis improves chemotherapy.
|
|
|
Authors
|
|
J.L.Wojtaszek,
N.Chatterjee,
J.Najeeb,
A.Ramos,
M.Lee,
K.Bian,
J.Y.Xue,
B.A.Fenton,
H.Park,
D.Li,
M.T.Hemann,
J.Hong,
G.C.Walker,
P.Zhou.
|
|
|
Ref.
|
|
Cell, 2019,
178,
152.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Intrinsic and acquired drug resistance and induction of secondary malignancies
limit successful chemotherapy. Because mutagenic translesion synthesis (TLS)
contributes to chemoresistance as well as treatment-induced mutations, targeting
TLS is an attractive avenue for improving chemotherapeutics. However,
development of small molecules with high specificity and in vivo efficacy for
mutagenic TLS has been challenging. Here, we report the discovery of a
small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing
recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly
featureless surface of REV1 that interacts with the REV7 subunit of POL ζ.
Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7
interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances
cisplatin-induced toxicity in cultured human and mouse cell lines.
Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft
human melanomas in mice, establishing a framework for developing TLS inhibitors
as a novel class of chemotherapy adjuvants.
|
|
|
|
|
|
|
