Seliciclib
Encyclopedia
R-roscovitine is a trial drug
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
.
Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), leukemia
, HIV
infection, herpes simplex
infection, 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. Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.
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. In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients. 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
".
Seliciclib is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia. Seliciclib has been shown to inhibit RNA polymerase II
-dependent transcription
and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1).
Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV
and preventing the replication of Herpes simplex
virus.
Seliciclib has been shown in vitro to induce apoptosis
in neutrophil granulocytes. 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 glucocorticoid
s which often have serious side effects.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
in the family of pharmacological cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
, CDK7 and CDK9
CDK9
CDK9 or cyclin-dependent kinase 9 is a cyclin-dependent kinase associated with P-TEFb.CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle...
, which alter the growth phase or state within the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
of treated cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Seliciclib is being developed by Cyclacel
Cyclacel
Cyclacel Pharmaceuticals Inc. Major shareholders include Magnetar Financial, Deerfield Management, Baker Brothers Advisors and the Federated Kaufmann Fund....
.
Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection, herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
infection, and the mechanisms of chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
disorders.
Seliciclib is a 2,6,9-substituted purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
analog. Its structure in complex with CDK2 was determined in 1996. Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.
Uses
Seliciclib has been found to produce apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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. In the current APPRAISE trial, the research drug is undergoing Phase IIb clinical trial as a monotherapy for NSCLC in third-line patients. The side-effects
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
reported in Phase I trials of Seliciclib for NSCLC were "nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting, transient elevations in serum creatinine and liver function parameters and transient hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
".
Seliciclib is also in clinical trials for B-cell lymphomas, including acute myelogenous leukemia. Seliciclib has been shown to inhibit RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
-dependent transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and down-regulation of myeloid cell leukaemia sequence 1 (Mcl-1).
Seliciclib is also a possible anti-viral agent. It causes the death of cells infected with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and preventing the replication of Herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
virus.
Seliciclib has been shown in vitro to induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in neutrophil granulocytes. 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
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
and arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
. These are usually treated with glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s which often have serious side effects.