title: Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.
abstract: 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.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Tinghu
authors: T
authors: Zhang
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Nicholas
authors: N
authors: Kwiatkowski
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Calla M
authors: CM
authors: Olson
authors: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors: Sarah E
authors: SE
authors: Dixon-Clarke
authors: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Brian J
authors: BJ
authors: Abraham
authors: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, Bonn, Germany.|Center of Advanced European Studies and Research, Bonn, Germany.
authors: Ann K
authors: AK
authors: Greifenberg
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Scott B
authors: SB
authors: Ficarro
authors: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors: Jonathan M
authors: 0000-0003-2858-8929
authors: JM
authors: Elkins
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Yanke
authors: Y
authors: Liang
authors: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Nancy M
authors: NM
authors: Hannett
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Pharmaceutical and Medicinal Chemistry, Department of Pharmacy, Saarland University, Saarbrücken, Germany.
authors: Theresa
authors: T
authors: Manz
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Mingfeng
authors: M
authors: Hao
authors: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Bartlomiej
authors: B
authors: Bartkowiak
authors: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
authors: Arno L
authors: AL
authors: Greenleaf
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Jarrod A
authors: JA
authors: Marto
authors: Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, Bonn, Germany.|Center of Advanced European Studies and Research, Bonn, Germany.
authors: Matthias
authors: M
authors: Geyer
authors: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors: Alex N
authors: 0000-0001-6757-0436
authors: AN
authors: Bullock
authors: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Richard A
authors: 0000-0001-8855-8647
authors: RA
authors: Young
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Nathanael S
authors: 0000-0001-5354-7403
authors: NS
authors: Gray
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000813:Anilides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000618758:THZ531; D016203:CDC2 Protein Kinase; C447339:CDK12 protein, human; C072262:CDK13 protein, human; D018844:Cyclin-Dependent Kinases; D003545:Cysteine