Chemistry: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);
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;

Short description: Chemical compound

Dinaciclib (SCH-727965) is an experimental drug that inhibits cyclin-dependent kinases (CDKs).^[1] It is being evaluated in clinical trials for various cancer indications.^[2]

Dinaciclib is being developed by Merck & Co. It was granted orphan drug status by the FDA in 2011.^[3]

Mechanisms of action

Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.^[4]
Dinaciclib (SCH727665) inhibits the unfolded protein response (UPR) through a CDK1 and CDK5-dependent mechanism.^[5]

Anti-tumoral action

In melanoma
- The anti-melanoma activity of dinaciclib is dependent on p53 signaling.^[6]
In chronic lymphocytic leukemia (CLL)
- Dinaciclib promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells.^[7]
In pancreatic cancer
- Dinaciclib inhibits pancreatic cancer growth and progression in murine xenograft models.^[8]
In osteosarcoma
- Dinacliclib induces the apoptosis of osteosarcoma cells.^[9]
- Apoptosis of osteosarcoma cultures can be induced by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.^[10]

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.^[11]

Clinical trials

Phase II
- Advanced breast cancer^[12]
- Non-small cell lung cancer (NSCLC)^[13]
- Multiple myeloma^[14]
- Advanced melanoma^[15]
Phase III
- A comparison of dinaciclib and ofatumumab for treatment of CLL^[16]

References

↑ "Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor". Molecular Cancer Therapeutics 9 (8): 2344–2353. August 2010. doi:10.1158/1535-7163.MCT-10-0324. PMID 20663931.
↑ "Cyclin-dependent kinase inhibitor therapy for hematologic malignancies". Expert Opinion on Investigational Drugs 22 (6): 723–738. June 2013. doi:10.1517/13543784.2013.789859. PMID 23647051.
↑ "Dinaciclib". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800026277.
↑ "Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains". ACS Chemical Biology 8 (11): 2360–2365. November 2013. doi:10.1021/cb4003283. PMID 24007471.
↑ "Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism". Molecular Cancer Therapeutics 13 (3): 662–674. March 2014. doi:10.1158/1535-7163.MCT-13-0714. PMID 24362465.
↑ "The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling". PLOS ONE 8 (3): e59588. 2013. doi:10.1371/journal.pone.0059588. PMID 23527225. Bibcode: 2013PLoSO...859588D.
↑ "The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells". Leukemia 26 (12): 2554–2557. December 2012. doi:10.1038/leu.2012.144. PMID 22791353.
↑ "Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models". Cancer Biology & Therapy 12 (7): 598–609. October 2011. doi:10.4161/cbt.12.7.16475. PMID 21768779.
↑ "The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells". Molecular Cancer Therapeutics 10 (6): 1018–1027. June 2011. doi:10.1158/1535-7163.MCT-11-0167. PMID 21490307.
↑ "Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor". Cell Death & Disease 4 (3): e566. March 2013. doi:10.1038/cddis.2013.101. PMID 23538447.
↑ "Satb2^Cre/+ mouse as a tool to investigate cell fate determination in the developing neocortex". Journal of Neuroscience Methods 291: 113–121. November 2017. doi:10.1016/j.jneumeth.2017.07.023. PMID 28782628.
↑ "Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer". Clinical Breast Cancer 14 (3): 169–176. June 2014. doi:10.1016/j.clbc.2013.10.016. PMID 24393852.
↑ "Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer". Lung Cancer 83 (2): 219–223. February 2014. doi:10.1016/j.lungcan.2013.11.020. PMID 24388167.
↑ Clinical trial number NCT01096342 for "Phase II Trial of CDK Inhibitor Sch 727965 in Multiple Myeloma" at ClinicalTrials.gov
↑ Clinical trial number Phase II Trial of Sch 727965 (NSC 747135) in Patients with Stage IV Melanoma NCT00937937A Phase II Trial of Sch 727965 (NSC 747135) in Patients with Stage IV Melanoma at ClinicalTrials.gov
↑ Clinical trial number NCT01580228 for "A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib or Ofatumumab in Subjects with Refractory Chronic Lymphocytic Leukemia" at ClinicalTrials.gov

External links

dinaciclib at the US National Library of Medicine Medical Subject Headings (MeSH)

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[1] "Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor". Molecular Cancer Therapeutics 9 (8): 2344–2353. August 2010. doi:10.1158/1535-7163.MCT-10-0324. PMID 20663931.

[pmid23647051-2] "Cyclin-dependent kinase inhibitor therapy for hematologic malignancies". Expert Opinion on Investigational Drugs 22 (6): 723–738. June 2013. doi:10.1517/13543784.2013.789859. PMID 23647051.

[Adis-3] "Dinaciclib". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800026277.

[4] "Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains". ACS Chemical Biology 8 (11): 2360–2365. November 2013. doi:10.1021/cb4003283. PMID 24007471.

[5] "Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism". Molecular Cancer Therapeutics 13 (3): 662–674. March 2014. doi:10.1158/1535-7163.MCT-13-0714. PMID 24362465.

[6] "The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling". PLOS ONE 8 (3): e59588. 2013. doi:10.1371/journal.pone.0059588. PMID 23527225. Bibcode: 2013PLoSO...859588D.

[7] "The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells". Leukemia 26 (12): 2554–2557. December 2012. doi:10.1038/leu.2012.144. PMID 22791353.

[8] "Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models". Cancer Biology & Therapy 12 (7): 598–609. October 2011. doi:10.4161/cbt.12.7.16475. PMID 21768779.

[9] "The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells". Molecular Cancer Therapeutics 10 (6): 1018–1027. June 2011. doi:10.1158/1535-7163.MCT-11-0167. PMID 21490307.

[10] "Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor". Cell Death & Disease 4 (3): e566. March 2013. doi:10.1038/cddis.2013.101. PMID 23538447.

[11] "Satb2^Cre/+ mouse as a tool to investigate cell fate determination in the developing neocortex". Journal of Neuroscience Methods 291: 113–121. November 2017. doi:10.1016/j.jneumeth.2017.07.023. PMID 28782628.

[12] "Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer". Clinical Breast Cancer 14 (3): 169–176. June 2014. doi:10.1016/j.clbc.2013.10.016. PMID 24393852.

[13] "Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer". Lung Cancer 83 (2): 219–223. February 2014. doi:10.1016/j.lungcan.2013.11.020. PMID 24388167.

[14] Clinical trial number NCT01096342 for "Phase II Trial of CDK Inhibitor Sch 727965 in Multiple Myeloma" at ClinicalTrials.gov

[15] Clinical trial number Phase II Trial of Sch 727965 (NSC 747135) in Patients with Stage IV Melanoma NCT00937937A Phase II Trial of Sch 727965 (NSC 747135) in Patients with Stage IV Melanoma at ClinicalTrials.gov

[16] Clinical trial number NCT01580228 for "A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib or Ofatumumab in Subjects with Refractory Chronic Lymphocytic Leukemia" at ClinicalTrials.gov

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