Seliciclib

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Contents

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
PubChem CID
UNII
  • InChI=1S/C19H26N6O/c1-4-15(11-26)22-19-23-17(20-10-14-8-6-5-7-9-14)16-18(24-19)25(12-21-16)13(2)3/h5-9,12-13,15,26H,4,10-11H2,1-3H3,(H2,20,22,23,24)/t15-/m1/s1 X mark.svgN
    Key: BTIHMVBBUGXLCJ-OAHLLOKOSA-N X mark.svgN
  • InChI=1/C19H26N6O/c1-4-15(11-26)22-19-23-17(20-10-14-8-6-5-7-9-14)16-18(24-19)25(12-21-16)13(2)3/h5-9,12-13,15,26H,4,10-11H2,1-3H3,(H2,20,22,23,24)/t15-/m1/s1
    Key: BTIHMVBBUGXLCJ-OAHLLOKOBS
  • CC[C@H](CO)NC1=NC(=C2C(=N1)N(C=N2)C(C)C)NCC3=CC=CC=C3
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

p21 Protein

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">Cyclin E</span> Member of the cyclin family

Cyclin E is a member of the cyclin family.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

<span class="mw-page-title-main">Cyclin-dependent kinase inhibitor protein</span> Protein which inhibits cyclin-dependent kinase

A cyclin-dependent kinase inhibitor protein(also known as CKIs, CDIs, or CDKIs) is a protein that inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the processes of DNA synthesis, mitosis, and cytokines control one another. When a malfunction hinders the successful completion of DNA synthesis in the G1 phase, it triggers a signal that delays or halts the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.

<span class="mw-page-title-main">Cyclin-dependent kinase 1</span> Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<span class="mw-page-title-main">CDKN1B</span> Protein-coding gene in humans

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

<span class="mw-page-title-main">Cyclin-dependent kinase 7</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the CDK7 gene.

<span class="mw-page-title-main">Cyclin A2</span> Protein-coding gene in the species Homo sapiens

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.

<span class="mw-page-title-main">Cyclin-dependent kinase 3</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 3 is an enzyme that in humans is encoded by the CDK3 gene.

<span class="mw-page-title-main">CDKN3</span> Protein-coding gene in humans

Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

<span class="mw-page-title-main">Pritelivir</span> Chemical compound

Pritelivir is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.

<span class="mw-page-title-main">Dinaciclib</span> Chemical compound

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

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.
  2. ↑ Noel S, Faveau C, Norez C, Rogier C, Mettey Y, Becq F (2006). "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. doi:10.1124/jpet.106.104521. PMID   16829626. S2CID   1554921.
  3. ↑ De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH (1997). "Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine". Eur J Biochem. 243 (1–2): 518–526. doi: 10.1111/j.1432-1033.1997.0518a.x . PMID   9030780.
  4. 1 2 "Cyclacel Begins a Phase IIb Randomized Trial of Seliciclib for Previously Treated Non-Small Cell Lung Cancer". BIOWIRE. June 29, 2006.
  5. 1 2 "Cyclacel Reports Interim Seliciclib Phase IIa Data at 2005 ASCO". Business Wire. May 15, 2005.
  6. ↑ "Cyclacel Pharmaceuticals Reports Second Quarter 2006 Financial Results". Business Wire. August 14, 2006.
  7. ↑ MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR (2005). "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. 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, Nikhil C. Munshi, Simon R. Green, Kenneth C. Anderson (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. PMC   1895150 . PMID   15827128.
  9. ↑ Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C (2006). "Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis". Nature Medicine . 12 (9): 1056–1064. doi:10.1038/nm1468. PMID   16951685. S2CID   5875865.
  10. ↑ Tomov N, Surchev L, Wiedenmann C, Döbrössy M, Nikkhah G (August 2019). "Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts". Experimental Neurology. 318: 135–144. doi:10.1016/j.expneurol.2019.04.013. PMID   31028828. S2CID   129946710.
  11. ↑ Menn B, Bach S, Blevins TL, Campbell M, Meijer L, Timsit S (2010-08-12). Manzoni OJ (ed.). "Delayed Treatment with Systemic (S)-Roscovitine Provides Neuroprotection and Inhibits In Vivo CDK5 Activity Increase in Animal Stroke Models". PLOS ONE. 5 (8): e12117. Bibcode:2010PLoSO...512117M. doi: 10.1371/journal.pone.0012117 . ISSN   1932-6203. PMC   2920814 . PMID   20711428.
  12. ↑ Rousselet E, Létondor A, Menn B, Courbebaisse Y, Quillé ML, Timsit S (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". Journal of Cerebral Blood Flow & Metabolism. 38 (6): 1070–1084. doi:10.1177/0271678X17712163. ISSN   0271-678X. PMC   5998998 . PMID   28569655.
  13. ↑ Pandey V, Ranjan N, Narne P, Babu PP (2019-03-21). "Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis". Scientific Reports. 9 (1): 5012. Bibcode:2019NatSR...9.5012P. doi:10.1038/s41598-019-41380-1. ISSN   2045-2322. PMC   6428853 . PMID   30899038.
  14. ↑ Sadaie MR, Mayner R, Doniger J (January 2004). "A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics". Antiviral Research. 61 (1): 1–18. doi:10.1016/j.antiviral.2003.09.004. PMID   14670589.
  15. ↑ Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao SH (2006). "Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics". Curr Pharm Des. 12 (16): 1949–61. doi:10.2174/138161206777442083. PMID   16787240.
  16. ↑ Agbottah E, de La Fuente C, Nekhai S, Barnett A, Gianella-Borradori A, Pumfery A, Kashanchi F (28 January 2005). "Antiviral activity of CYC202 in HIV-1-infected cells". J. Biol. Chem. 280 (4): 3029–42. doi: 10.1074/jbc.M406435200 . PMID   15531588.
  17. ↑ Schang LM, Rosenberg A, Schaffer PA (2000). "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. doi:10.1128/JVI.74.5.2107-2120.2000. PMC   111691 . PMID   10666240.
  18. ↑ Diwan P, Lacasse JJ, Schang LM (2004). "Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors". J. Virol. 78 (17): 9352–9365. doi:10.1128/JVI.78.17.9352-9365.2004. PMC   506918 . PMID   15308730.
  19. ↑ Doree M, Galas S (1994). "The cyclin-dependent protein kinases and the control of cell division". FASEB J. 8 (14): 1114–1121. doi: 10.1096/fasebj.8.14.7958616 . PMID   7958616. S2CID   3069118.
  20. ↑ Yu, Alan S. L., Chertow, Glenn M., Luyckx, Valérie A., Marsden, Philip A., Skorecki, Karl, Taal, Maarten W., eds. (25 September 2019). Brenner & Rector's the kidney. Elsevier Health Sciences. ISBN   978-0-323-55085-7. OCLC   1122857051.
  21. ↑ Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, Chiao J, Armour S, Frame S, Green SR, Gianella-Borradori A, Diéras V, Raymond E (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.
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