Dinaciclib

Dinaciclib
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
Synonyms	SCH-727965
CAS Number	779353-01-4
PubChem (CID)	46926350
IUPHAR/BPS	7379
ChemSpider	25027387
ChEMBL	CHEMBL2103840
PDB ligand ID	1QK (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₁H₂₈N₆O₂
Molar mass	396.50 g·mol⁻¹
3D model (Jmol)	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).^[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 MP, Doll R, Nomeir A, Windsor W, Fischmann T, Wang Y, Oft M, Chen T, Kirschmeier P, Lees EM (Aug 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 (Jun 2013). "Cyclin-dependent kinase inhibitor therapy for hematologic malignancies". Expert Opinion on Investigational Drugs. 22 (6): 723–38. doi:10.1517/13543784.2013.789859. PMC 4039040. PMID 23647051.
↑ Martin MP, Olesen SH, Georg GI, Schönbrunn E (Nov 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 TK, Grant S (Mar 2014). "Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism". Molecular Cancer Therapeutics. 13 (3): 662–74. doi:10.1158/1535-7163.MCT-13-0714. PMID 24362465.
↑ Desai BM, Villanueva J, Nguyen TT, Lioni M, Xiao M, Kong J, Krepler C, Vultur A, Flaherty KT, Nathanson KL, Smalley KS, 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 AJ, Yeh YY, Smith LL, Wagner AJ, Hessler J, Gupta S, Flynn J, Jones J, Zhang X, Bannerji R, Grever MR, Byrd JC (Dec 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 NA, Dadon T, Alvarez H, Fendrich V, Rajeshkumar NV, Matsui W, Brossart P, Hidalgo M, Bannerji R, Maitra A, Nelkin BD (Oct 2011). "Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models". Cancer Biology & Therapy. 12 (7): 598–609. doi:10.4161/cbt.12.7.16475. PMC 3218385. PMID 21768779.
↑ Fu W, Ma L, Chu B, Wang X, Bui MM, Gemmer J, Altiok S, Pledger WJ (Jun 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 SS, Ma L, Chu B, Bui MM, Reed D, Pledger WJ (2013). "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. doi:10.1038/cddis.2013.101. PMC 3613821. PMID 23538447.
↑ Nemunaitis JJ, Small KA, Kirschmeier P, Zhang D, Zhu Y, Jou YM, Statkevich P, Yao SL, 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 MM, Joy AA, Mita A, Sankhala K, Jou YM, Zhang D, Statkevich P, Zhu Y, Yao SL, Small K, Bannerji R, Shapiro CL (Jun 2014). "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 JJ, Nemunaitis J, Joy AA, Martin JC, Jou YM, Zhang D, Statkevich P, Yao SL, Zhu Y, Zhou H, Small K, Bannerji R, Edelman MJ (Feb 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)

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