Chemistry:Seliciclib

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Seliciclib
Seliciclib structure.svg
Names
Preferred IUPAC name
(2R)-2-{[6-(Benzylamino)-9-(propan-2-yl)-9H-purin-2-yl]amino}butan-1-ol
Other names
Roscovitine; CYC202
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
MeSH roscovitine
UNII
Properties
C19H26N6O
Molar mass 354.458 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Seliciclib (roscovitine or CYC202) is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.This is a phase II, dose ranging, multicenter, randomized, double-blind, placebo-controlled study.

The aim of this study is to assess the safety of increasing doses of roscovitine administered orally for 4 cycles of 4 consecutive days (treatment "on") separated by a 3 days treatment free period (treatment "off") in adult CF subjects with Cystic Fibrosis carrying 2 Cystic Fibrosis causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa.

This study involved 36 Cystic Fibrosis patients: 24 treated and 12 controls.[1]

Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), Cushing's disease, leukemia, HIV infection, Parkinson’s disease, herpes simplex infection, cystic fibrosis[2] and the mechanisms of chronic inflammation disorders.

Seliciclib is a 2,6,9-substituted purine analog. Its structure in complex with CDK2 was determined in 1996.[3] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.[4]

Clinical trials and lab tests

Cancer treatment

Seliciclib has been found to produce apoptosis in treated cancerous cells of non-small cell lung cancer (NSCLC) and other cancers. Seliciclib has previously undergone Phase IIa clinical trials, in 240 NSCLC patients as a combined dose with existing first- and second-line treatments.[4][5] In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients.[6] The side-effects reported in Phase I trials of seliciclib for NSCLC were "nausea, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia".[5]

Immunological disorders

Seliciclib is also in clinical trials for B-cell lymphomas, including multiple myeloma. Seliciclib has been shown to inhibit RNA polymerase II-dependent transcription and down-regulation of the protein MCL1.[7][8]

Seliciclib has been shown in vitro to induce apoptosis in neutrophil granulocytes.[9] If this mechanism turns out to be safe, reliable and efficient in vivo, the drug could improve treatment of chronic inflammation diseases such as cystic fibrosis and arthritis. These are usually treated with glucocorticoids which often have serious side effects

Neurological therapies

In the nervous system, seliciclib has been shown to suppress microglial activation[10] and to provide some neuroprotection in animal models of cerebral ischemia.[11][12] Furthermore, it increases antitumor activity of temozolomide in treatment of glioblastoma multiforme and is considered as a possible therapeutic option for glioma.[13]

Antiviral effect

Seliciclib is also a possible antiviral agent. It causes the death of cells infected with HIV[14][15][16] and preventing the replication of herpes simplex virus.[17][18]

Ovum production

Seliciclib has been shown to cause parthenogenetic egg activation. However it does create abnormal second polar bodies and therefore possible aneuploid zygotes. Egg activation usually involves calcium oscillations however this does not happen with seliciclib. Seciclib causes egg activation by inhibiting protein kinases which results in the inactivation of the maturation promoting factor (MPF).[19]

Renal hypertrophy

Seliciclib reduces renal hypertrophy by 45% after 5/6 nephrectomy.[20]

Side effects

Causes severe side effects that can not be tolerated on daily bases. Side effects include hypokalemia and elevation of liver enzymes.[21] Due to these side effects Seliciclib has not been approved by the USFDA.

References

  1. ↑ "A Phase II, Dose Ranging, Multicenter, Double-blind, Placebo Controlled Study to Evaluate Safety and Effects of (R)-Roscovitine in Adults Subjects with Cystic Fibrosis, Carrying 2 Cystic Fibrosis Causing Mutations with at Least One F508del-CFTR Mutation and Chronically Infected with Pseudomonas Aeruginosa, a Study Involving 36 CF Patients (24 Treated, 12 Controls). ROSCO-CF.". 11 December 2018. https://clinicaltrials.gov/ct2/show/study/NCT02649751. 
  2. ↑ "Discovery of pyrrolo[2,3-b]pyrazines derivatives as submicromolar affinity activators of wild type, G551D, and F508del cystic fibrosis transmembrane conductance regulator chloride channels". J Pharmacol Exp Ther 319 (1): 349–59. 2006. doi:10.1124/jpet.106.104521. PMID 16829626. 
  3. ↑ "Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine". Eur J Biochem 243 (1–2): 518–526. 1997. doi:10.1111/j.1432-1033.1997.0518a.x. PMID 9030780. 
  4. ↑ 4.0 4.1 "Cyclacel Begins a Phase IIb Randomized Trial of Seliciclib for Previously Treated Non-Small Cell Lung Cancer". BIOWIRE. June 29, 2006. http://www.genengnews.com/news/bnitem.aspx?name=3002660. 
  5. ↑ 5.0 5.1 "Cyclacel Reports Interim Seliciclib Phase IIa Data at 2005 ASCO". Business Wire. May 15, 2005. http://www.findarticles.com/p/articles/mi_m0EIN/is_2005_May_15/ai_n13718674. 
  6. ↑ "Cyclacel Pharmaceuticals Reports Second Quarter 2006 Financial Results". Business Wire. August 14, 2006. http://www.nasdaq.com//aspxcontent/newsstory.aspx?selected=CYCC&symbol=CYCC&textpath=20060814%5CACQBIZ200608141711BIZWIRE%5FUSPR%5F%5F%5F%5F%5FBW6007%2Ehtm&cdtime=08%2F14%2F2006+5%3A11PM. 
  7. ↑ "Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1". Cancer Research 65 (12): 5399–5407. 2005. doi:10.1158/0008-5472.CAN-05-0233. PMID 15958589. 
  8. ↑ Noopur Raje; Shaji Kumar; Teru Hideshima; Aldo Roccaro; Kenji Ishitsuka; Hiroshi Yasui; Norihiko Shiraishi; Dharminder Chauhan et al. (August 1, 2005). "Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma". Blood 106 (3): 1042–1047. doi:10.1182/blood-2005-01-0320. PMID 15827128. 
  9. ↑ "Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis". Nature Medicine 12 (9): 1056–1064. 2006. doi:10.1038/nm1468. PMID 16951685. 
  10. ↑ Tomov, Nikola; Surchev, Lachezar; Wiedenmann, Clemens; Döbrössy, Máté; Nikkhah, Guido (August 2019). "Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts" (in en). Experimental Neurology 318: 135–144. doi:10.1016/j.expneurol.2019.04.013. PMID 31028828. https://linkinghub.elsevier.com/retrieve/pii/S0014488618304254. 
  11. ↑ Menn, Bénédicte; Bach, Stéphane; Blevins, Teri L.; Campbell, Mark; Meijer, Laurent; Timsit, Serge (2010-08-12). Manzoni, Olivier Jacques. ed. "Delayed Treatment with Systemic (S)-Roscovitine Provides Neuroprotection and Inhibits In Vivo CDK5 Activity Increase in Animal Stroke Models" (in en). PLOS ONE 5 (8): e12117. doi:10.1371/journal.pone.0012117. ISSN 1932-6203. PMID 20711428. Bibcode: 2010PLoSO...512117M. 
  12. ↑ Rousselet, Estelle; Létondor, Anne; Menn, Bénédicte; Courbebaisse, Yann; Quillé, Marie-Lise; Timsit, Serge (June 2018). "Sustained (S)-roscovitine delivery promotes neuroprotection associated with functional recovery and decrease in brain edema in a randomized blind focal cerebral ischemia study" (in en). Journal of Cerebral Blood Flow & Metabolism 38 (6): 1070–1084. doi:10.1177/0271678X17712163. ISSN 0271-678X. PMID 28569655. 
  13. ↑ Pandey, Vimal; Ranjan, Nikhil; Narne, Parimala; Babu, Phanithi Prakash (2019-03-21). "Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis" (in en). Scientific Reports 9 (1): 5012. doi:10.1038/s41598-019-41380-1. ISSN 2045-2322. PMID 30899038. Bibcode: 2019NatSR...9.5012P. 
  14. ↑ "A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics". Antiviral Research 61 (1): 1–18. January 2004. doi:10.1016/j.antiviral.2003.09.004. PMID 14670589. 
  15. ↑ "Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics". Curr Pharm Des 12 (16): 1949–61. 2006. doi:10.2174/138161206777442083. PMID 16787240. 
  16. ↑ "Antiviral activity of CYC202 in HIV-1-infected cells". J. Biol. Chem. 280 (4): 3029–42. 28 January 2005. doi:10.1074/jbc.M406435200. PMID 15531588. 
  17. ↑ "Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins". J. Virol. 74 (5): 2107–20. 2000. doi:10.1128/JVI.74.5.2107-2120.2000. PMID 10666240. 
  18. ↑ "Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors". J. Virol. 78 (17): 9352–9365. 2004. doi:10.1128/JVI.78.17.9352-9365.2004. PMID 15308730. 
  19. ↑ "The cyclin-dependent protein kinases and the control of cell division". FASEB J 8 (14): 1114–1121. 1994. doi:10.1096/fasebj.8.14.7958616. PMID 7958616. 
  20. ↑ Brenner & Rector's the kidney. Elsevier Health Sciences. 25 September 2019. ISBN 978-0-323-55085-7. OCLC 1122857051. http://worldcat.org/oclc/1122857051. 
  21. ↑ Le Tourneau, Christophe; Faivre, Sandrine; Laurence, Valérie; Delbaldo, Catherine; Vera, Karina; Girre, Veronique; Chiao, Judy; Armour, Sian et al. (December 2010). "Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies". European Journal of Cancer 46 (18): 3243–3250. doi:10.1016/j.ejca.2010.08.001. ISSN 1879-0852. PMID 20822897. https://pubmed.ncbi.nlm.nih.gov/20822897/. 



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