Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBJR4L)

• DTT Name: Cyclin-dependent kinase 8 (CDK8)
• Synonyms: Protein kinase K35; Mediator of RNA polymerase II transcription subunit CDK8; Mediator complex subunit CDK8; Cell division protein kinase 8
• Gene Name: CDK8
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CDK8_HUMAN
• TTD ID: T10822
• EC Number: EC 2.7.11.22
• Sequence:
  MDYDFKVKLSSERERVEDLFEYEGCKVGRGTYGHVYKAKRKDGKDDKDYALKQIEGTGIS
  MSACREIALLRELKHPNVISLQKVFLSHADRKVWLLFDYAEHDLWHIIKFHRASKANKKP
  VQLPRGMVKSLLYQILDGIHYLHANWVLHRDLKPANILVMGEGPERGRVKIADMGFARLF
  NSPLKPLADLDPVVVTFWYRAPELLLGARHYTKAIDIWAIGCIFAELLTSEPIFHCRQED
  IKTSNPYHHDQLDRIFNVMGFPADKDWEDIKKMPEHSTLMKDFRRNTYTNCSLIKYMEKH
  KVKPDSKAFHLLQKLLTMDPIKRITSEQAMQDPYFLEDPLPTSDVFAGCQIPYPKREFLT
  EEEPDDKGDKKNQQQQQGNNHTNGTGHPGNQDSSHTQGPPLKKVRVVPPTTTSGGLIMTS
  DYQRSNPHAAYPNPGPSTSQPQSSMGYSATSQQPPQYSHQTHRY
• Function: Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  SMAD2/SMAD3 (R-HSA-2173796)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SEL120	DMHCUZV	Acute myeloid leukaemia	2A60	Phase 1	[2]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Macrocycle derivative 14	DMXSRPH	N. A.	N. A.	Patented	[1]
Tricyclic benzimidazole derivative 1	DM5SD9E	N. A.	N. A.	Patented	[1]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CCT251545	DMNA9KW	Colorectal cancer	2B91.Z	Preclinical	[3]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Oxindole 16 (compound 3)	DMM5208	Discovery agent	N.A.	Investigative	[4]
Oxindole 94	DMPFD6Y	Pain	MG30-MG3Z	Investigative	[4]

References

• [1] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [2] Clinical pipeline report, company report or official report of Ryvu Therapeutics.
• [3] Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018 May;17(5):353-377.
• [4] Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.