Dinaciclib

Systematic (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
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	779353-01-4
PubChem	CID 46926350
ChemSpider	25027387
ChEMBL	CHEMBL2103840
Synonyms	SCH-727965
Chemical data
Formula	C₂₁H₂₈N₆O₂
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.^[1] It is being evaluated in clinical trials for various cancer indications.^[2]

Mechanisms of action

Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.^[3]
Dinaciclib (SCH727665) inhibits the unfolded protein response (UPR) through a CDK1 and CDK5-dependent mechanism.^[4]

Anti-tumoral action

In melanoma
- The anti-melanoma activity of dinaciclib is dependent on p53 signaling.^[5]

In chronic lymphocytic leukemia (CLL)
- Dinaciclib promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells.^[6]

In pancreatic cancer
- Dinaciclib inhibits pancreatic cancer growth and progression in murine xenograft models.^[7]

In osteosarcoma
- Dinacliclib induces the apoptosis of osteosarcoma cells.^[8]
- Apoptosis of osteosarcoma cultures can be induced by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.^[9]

Clinical trials

Phase 1^[10]
Phase 2
- Advanced breast cancer^[11]
- Non-small cell lung cancer (NSCLC)^[12]

References

↑ Parry, D; Guzi, T; Shanahan, F; Davis, N; Prabhavalkar, D; Wiswell, D; Seghezzi, W; Paruch, K; Dwyer, M. P.; Doll, R; Nomeir, A; Windsor, W; Fischmann, T; Wang, Y; Oft, M; Chen, T; Kirschmeier, P; Lees, E. M. (2010). "Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor". Molecular Cancer Therapeutics 9 (8): 2344–53. doi:10.1158/1535-7163.MCT-10-0324. PMID 20663931.
↑ Bose P, Simmons GL, Grant S (2013). "Cyclin-dependent kinase inhibitor therapy for hematologic malignancies". Expert Opin Investig Drugs 22 (6): 723–38. doi:10.1517/13543784.2013.789859. PMC 4039040. PMID 23647051.
↑ Martin, M. P.; Olesen, S. H.; Georg, G. I.; Schönbrunn, E (2013). "Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains". ACS Chemical Biology 8 (11): 2360–5. doi:10.1021/cb4003283. PMC 3846258. PMID 24007471.
↑ Nguyen, T. K.; Grant, S (2013). "Dinaciclib (SCH727665) inhibits the unfolded protein response (UPR) through a CDK1 and CDK5-dependent mechanism". Molecular Cancer Therapeutics 13 (3): 662–74. doi:10.1158/1535-7163.MCT-13-0714. PMID 24362465.
↑ Desai, B. M.; Villanueva, J; Nguyen, T. T.; Lioni, M; Xiao, M; Kong, J; Krepler, C; Vultur, A; Flaherty, K. T.; Nathanson, K. L.; Smalley, K. S.; Herlyn, M (2013). "The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling". PLoS ONE 8 (3): e59588. doi:10.1371/journal.pone.0059588. PMC 3601112. PMID 23527225.
↑ Johnson, A. J.; Yeh, Y. Y.; Smith, L. L.; Wagner, A. J.; Hessler, J; Gupta, S; Flynn, J; Jones, J; Zhang, X; Bannerji, R; Grever, M. R.; Byrd, J. C. (2012). "The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells". Leukemia 26 (12): 2554–7. doi:10.1038/leu.2012.144. PMC 3645353. PMID 22791353.
↑ Feldmann, G; Mishra, A; Bisht, S; Karikari, C; Garrido-Laguna, I; Rasheed, Z; Ottenhof, N. A.; Dadon, T; Alvarez, H; Fendrich, V; Rajeshkumar, N. V.; Matsui, W; Brossart, P; Hidalgo, M; Bannerji, R; Maitra, A; Nelkin, B. D. (2011). "Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models". Cancer biology & therapy 12 (7): 598–609. PMC 3218385. PMID 21768779.
↑ Fu, W; Ma, L; Chu, B; Wang, X; Bui, M. M.; Gemmer, J; Altiok, S; Pledger, W. J. (2011). "The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells". Molecular Cancer Therapeutics 10 (6): 1018–27. doi:10.1158/1535-7163.MCT-11-0167. PMID 21490307.
↑ Fu, W; Sharma, S. S.; Ma, L; Chu, B; Bui, M. M.; Reed, D; Pledger, W. J. (2013). "Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor". Cell Death and Disease 4 (3): e566. doi:10.1038/cddis.2013.101. PMC 3613821. PMID 23538447.
↑ Nemunaitis, J. J.; Small, K. A.; Kirschmeier, P; Zhang, D; Zhu, Y; Jou, Y. M.; Statkevich, P; Yao, S. L.; Bannerji, R (2013). "A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies". Journal of Translational Medicine 11 (1): 259. doi:10.1186/1479-5876-11-259. PMC 3853718. PMID 24131779.
↑ Mita, M; Joy, A. A.; Mita, A; Sankhala, K; Jou, Y. M.; Zhang, D; Statkevich, P; Zhu, Y; Yao, S. L.; Small, K; Bannerji, R; Shapiro, C. L. (2013). "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): 169–76. doi:10.1016/j.clbc.2013.10.016. PMID 24393852.
↑ Stephenson, J. J.; Nemunaitis, J; Joy, A. A.; Martin, J. C.; Jou, Y. M.; Zhang, D; Statkevich, P; Yao, S. L.; Zhu, Y; Zhou, H; Small, K; Bannerji, R; Edelman, M. J. (2014). "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): 219–23. doi:10.1016/j.lungcan.2013.11.020. PMID 24388167.

External links

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