 |
PDBsum entry 7nxk
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
7nxk
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure-Activity relationship study of thz531 derivatives enables the discovery of bsj-01-175 as a dual cdk12/13 covalent inhibitor with efficacy in ewing sarcoma.
|
|
|
Authors
|
|
B.Jiang,
J.Jiang,
I.H.Kaltheuner,
A.B.Iniguez,
K.Anand,
F.M.Ferguson,
S.B.Ficarro,
B.K.A.Seong,
A.K.Greifenberg,
S.Dust,
N.P.Kwiatkowski,
J.A.Marto,
K.Stegmaier,
T.Zhang,
M.Geyer,
N.S.Gray.
|
|
|
Ref.
|
|
Eur J Med Chem, 2021,
221,
113481.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Development of inhibitors targeting CDK12/13 is of increasing interest as a
potential therapy for cancers as these compounds inhibit transcription of DNA
damage response (DDR) genes. We previously described THZ531, a covalent
inhibitor with selectivity for CDK12/13. In order to elucidate
structure-activity relationship (SAR), we have undertaken a medicinal chemistry
campaign and established a focused library of THZ531 analogs. Among these
analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA
polymerase II phosphorylation, and downregulation of CDK12-targeted genes in
cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a
structural rational for selective targeting of Cys1039 located in a C-terminal
extension from the kinase domain. With moderate pharmacokinetic properties,
BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a
patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day,
intraperitoneal administration. Taken together, BSJ-01-175 represents the first
selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.
|
|
|
|
|
|
|
