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PDBsum entry 5acb
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References listed in PDB file
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Key reference
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Title
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Covalent targeting of remote cysteine residues to develop cdk12 and cdk13 inhibitors.
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Authors
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T.Zhang,
N.Kwiatkowski,
C.M.Olson,
S.E.Dixon-Clarke,
B.J.Abraham,
A.K.Greifenberg,
S.B.Ficarro,
J.M.Elkins,
Y.Liang,
N.M.Hannett,
T.Manz,
M.Hao,
B.Bartkowiak,
A.L.Greenleaf,
J.A.Marto,
M.Geyer,
A.N.Bullock,
R.A.Young,
N.S.Gray.
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Ref.
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Nat Chem Biol, 2016,
12,
876-884.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the
regulation of gene transcription. However, the absence of CDK12 and CDK13
inhibitors has hindered the ability to investigate the consequences of their
inhibition in healthy cells and cancer cells. Here we describe the rational
design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531.
Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531
irreversibly targets a cysteine located outside the kinase domain. THZ531 causes
a loss of gene expression with concurrent loss of elongating and
hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially
decreases the expression of DNA damage response genes and key
super-enhancer-associated transcription factor genes. Coincident with
transcriptional perturbation, THZ531 dramatically induced apoptotic cell death.
Small molecules capable of specifically targeting CDK12 and CDK13 may thus help
identify cancer subtypes that are particularly dependent on their kinase
activities.
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