Dinaciclib

Dinaciclib

Clinical data
Other names	SCH-727965
Legal status
Legal status	Investigational
Identifiers
IUPAC name (S)-3-(((3-Ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)pyridine 1-oxide
CAS Number	779353-01-4
PubChem CID	46926350
IUPHAR/BPS	7379
ChemSpider	25027387
UNII	4V8ECV0NBQ
KEGG	D09604
ChEMBL	ChEMBL2103840
PDB ligand	1QK (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID90999131
ECHA InfoCard	100.246.885
Chemical and physical data
Formula	C21H28N6O2
Molar mass	396.495 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCC[C@H]4CCO
InChI InChI=1S/C21H28N6O2/c1-2-17-14-23-27-19(22-13-16-6-5-9-25(29)15-16)12-20(24-21(17)27)26-10-4-3-7-18(26)8-11-28/h5-6,9,12,14-15,18,22,28H,2-4,7-8,10-11,13H2,1H3/t18-/m0/s1 Key:PIMQWRZWLQKKBJ-SFHVURJKSA-N

Dinaciclib (SCH-727965) is an experimental drug that inhibits cyclin-dependent kinases (CDKs). It is being evaluated in clinical trials for various cancer indications.

Dinaciclib is being developed by Merck & Co. It was granted orphan drug status by the FDA in 2011.

Mechanisms of action

• Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.
• Dinaciclib (SCH727665) inhibits the unfolded protein response (UPR) through a CDK1 and CDK5-dependent mechanism.

Anti-tumoral action

• In melanoma
  • The anti-melanoma activity of dinaciclib is dependent on p53 signaling.
• In chronic lymphocytic leukemia (CLL)
  • Dinaciclib promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells.
• In pancreatic cancer
  • Dinaciclib inhibits pancreatic cancer growth and progression in murine xenograft models.
• In osteosarcoma
  • Dinacliclib induces the apoptosis of osteosarcoma cells.
  • Apoptosis of osteosarcoma cultures can be induced by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.

Role in developing neurons

In primary cultured neurons, dinaciclib regulates neurogenesis, where it reduces expression of upper layer marker Satb2, and induces CTIP2, expressed in neurons of deeper layers.

Clinical trials

• Phase II
  • Advanced breast cancer
  • Non-small cell lung cancer (NSCLC)
  • Multiple myeloma
  • Advanced melanoma
• Phase III
  • A comparison of dinaciclib and ofatumumab for treatment of CLL

External links

• dinaciclib at the U.S. National Library of Medicine Medical Subject Headings (MeSH)