Dinaciclib

Last updated
Dinaciclib
Dinaciclib.svg
Clinical data
Other namesSCH-727965
Legal status
Legal status
  • Investigational
Identifiers
  • (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
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.246.885 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H28N6O2
Molar mass 396.495 g·mol−1
3D model (JSmol)
  • CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCC[C@H]4CCO
  • 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]

Contents

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

Mechanisms of action

Anti-tumoral action


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

References

  1. ↑ Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, et al. (August 2010). "Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor". Molecular Cancer Therapeutics. 9 (8): 2344–2353. doi: 10.1158/1535-7163.MCT-10-0324 . PMID   20663931.
  2. ↑ Bose P, Simmons GL, Grant S (June 2013). "Cyclin-dependent kinase inhibitor therapy for hematologic malignancies". Expert Opinion on Investigational Drugs. 22 (6): 723–738. doi:10.1517/13543784.2013.789859. PMC   4039040 . PMID   23647051.
  3. ↑ "Dinaciclib". AdisInsight. Springer Nature Switzerland AG. Retrieved 31 January 2017.
  4. ↑ Martin MP, Olesen SH, Georg GI, Schönbrunn E (November 2013). "Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains". ACS Chemical Biology. 8 (11): 2360–2365. doi:10.1021/cb4003283. PMC   3846258 . PMID   24007471.
  5. ↑ Nguyen TK, Grant S (March 2014). "Dinaciclib (SCH727965) inhibits the unfolded protein response through a CDK1- and 5-dependent mechanism". Molecular Cancer Therapeutics. 13 (3): 662–674. doi:10.1158/1535-7163.MCT-13-0714. PMC   3970263 . PMID   24362465.
  6. ↑ Desai BM, Villanueva J, Nguyen TT, Lioni M, Xiao M, Kong J, et al. (2013). "The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling". PLOS ONE. 8 (3) e59588. Bibcode:2013PLoSO...859588D. doi: 10.1371/journal.pone.0059588 . PMC   3601112 . PMID   23527225.
  7. ↑ Johnson AJ, Yeh YY, Smith LL, Wagner AJ, Hessler J, Gupta S, et al. (December 2012). "The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells". Leukemia. 26 (12): 2554–2557. doi:10.1038/leu.2012.144. PMC   3645353 . PMID   22791353.
  8. ↑ Feldmann G, Mishra A, Bisht S, Karikari C, Garrido-Laguna I, Rasheed Z, et al. (October 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.
  9. ↑ Fu W, Ma L, Chu B, Wang X, Bui MM, Gemmer J, et al. (June 2011). "The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells". Molecular Cancer Therapeutics. 10 (6): 1018–1027. doi:10.1158/1535-7163.MCT-11-0167. PMC   4727401 . PMID   21490307.
  10. ↑ Fu W, Sharma SS, Ma L, Chu B, Bui MM, Reed D, Pledger WJ (March 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.
  11. ↑ Ambrozkiewicz MC, Bessa P, Salazar-Lázaro A, Salina V, Tarabykin V (November 2017). "Satb2Cre/+ mouse as a tool to investigate cell fate determination in the developing neocortex". Journal of Neuroscience Methods. 291: 113–121. doi:10.1016/j.jneumeth.2017.07.023. PMID   28782628. S2CID   140208929.
  12. ↑ Mita MM, Joy AA, Mita A, Sankhala K, Jou YM, Zhang D, et al. (June 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): 169–176. doi:10.1016/j.clbc.2013.10.016. PMID   24393852.
  13. ↑ Stephenson JJ, Nemunaitis J, Joy AA, Martin JC, Jou YM, Zhang D, et al. (February 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): 219–223. 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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