Target Information

Target General Infomation
Target ID
T58470
Former ID
TTDR00224
Target Name
Cyclin-A2
Gene Name
CCNA2
Synonyms
Cyclin; Cyclin-A; PCNA; CCNA2
Target Type
Discontinued
Disease Retinoblastoma [ICD10: C69.2]
Function
Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'- 5' exonuclease and 3'-phosphodiesterase, but not apurinic- apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.
Target Validation
T58470
UniProt ID
P20248
Sequence
MLGNSAPGPATREAGSALLALQQTALQEDQENINPEKAAPVQQPRTRAALAVLKSGNPRG
LAQQQRPKTRRVAPLKDLPVNDEHVTVPPWKANSKQPAFTIHVDEAEKEAQKKPAESQKI
EREDALAFNSAISLPGPRKPLVPLDYPMDGSFESPHTMDMSIILEDEKPVSVNEVPDYHE
DIHTYLREMEVKCKPKVGYMKKQPDITNSMRAILVDWLVEVGEEYKLQNETLHLAVNYID
RFLSSMSVLRGKLQLVGTAAMLLASKFEEIYPPEVAEFVYITDDTYTKKQVLRMEHLVLK
VLTFDLAAPTVNQFLTQYFLHQQPANCKVESLAMFLGELSLIDADPYLKYLPSVIAGAAF
HLALYTVTGQSWPESLIRKTGYTLESLKPCLMDLHQTYLKAPQHAQQSIREKYKNSKYHG
VSLLNPPETLNL
Structure
1E9H; 1FIN; 1FVV; 1GY3; 1H1P; 1H1Q; 1H1R; 1H1S; 1H24; 1H25; 1H26; 1H27; 1H28; 1JST; 1JSU; 1OGU; 1OI9; 1OIU; 1OIY; 1OKV; 1OKW; 1OL1; 1OL2; 1P5E; 1PKD; 1QMZ; 1URC; 1VYW; 2BKZ; 2BPM; 2C4G; 2C5N; 2C5O; 2C5V; 2C5X; 2C6T; 2CCH; 2CCI; 2CJM; 2I40; 2IW6; 2IW8; 2IW9; 2UUE; 2UZB; 2UZD; 2UZE; 2UZL; 2V22; 2WEV; 2WFY; 2WHB; 2WIH; 2WIP; 2WMA; 2WMB; 2WPA; 2WXV; 2X1N; 3EID; 3EJ1; 3EOC; 3F5X; 4BCK; 4BCM; 4BCN; 4BCP; 4CFM; 4CFN; 4CFU; 4CFV; 4CFW; 4CFX; 4EOI; 4EOJ; 4EOK; 4EOL; 4EOM; 4EON; 4EOO; 4EOP; 4EOQ; 4EOR; 4EOS; 4FX3; 1AXC; 1U76; 1U7B; 1UL1; 1VYJ; 1VYM; 1W60; 2ZVK; 2ZVL; 2ZVM; 3P87; 3TBL; 3VKX; 3WGW
Drugs and Mode of Action
Drug(s) PD-0183812 Drug Info Terminated Retinoblastoma [547217]
Inhibitor 2,5-dichloro-N-p-tolylthiophene-3-sulfonamide Drug Info [551239]
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol Drug Info [528490]
4-(7-Butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol Drug Info [526504]
4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine Drug Info [528490]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info [528490]
6-(3-Amino-benzyloxy)-9H-purin-2-ylamine Drug Info [526389]
6-(3-Methyl-benzyloxy)-9H-purin-2-ylamine Drug Info [526389]
6-(Cyclohex-3-enylmethoxy)-9H-purin-2-ylamine Drug Info [526389]
6-Cyclohexylmethoxy-pyrimidine-2,4,5-triamine Drug Info [526489]
GW-8510 Drug Info [526991]
MERIOLIN 1 Drug Info [529275]
MERIOLIN 2 Drug Info [529275]
MERIOLIN 3 Drug Info [529275]
MERIOLIN 4 Drug Info [529275]
MERIOLIN 5 Drug Info [529275]
MERIOLIN 6 Drug Info [529275]
MERIOLIN 7 Drug Info [529275]
MERIOLIN 8 Drug Info [529275]
NU-2058 Drug Info [527129]
NU-6027 Drug Info [526489]
PD-0183812 Drug Info [525924]
PURVALANOLA Drug Info [529039]
RESCOVITINE Drug Info [530612]
Pathways
KEGG Pathway DNA replication
Base excision repair
Nucleotide excision repair
Mismatch repair
Cell cycle
Hepatitis B
HTLV-I infection
PathWhiz Pathway Nucleotide Excision Repair
Reactome E2F mediated regulation of DNA replication
G0 and Early G1
Phospho-APC/C mediated degradation of Cyclin A
Regulation of APC/C activators between G1/S and early anaphase
SCF(Skp2)-mediated degradation of p27/p21
Senescence-Associated Secretory Phenotype (SASP)
MSH6 (MutSalpha)
MSH3 (MutSbeta)
HDR through Homologous Recombination (HRR)
Processing of DNA double-strand break ends
Dual Incision in GG-NER
Dual incision in TC-NER
Gap-filling DNA repair synthesis and ligation in TC-NER
G2 Phase
Orc1 removal from chromatin
G1/S-Specific Transcription
Cyclin A/B1 associated events during G2/M transition
Cdk2-associated events at S phase entry
WikiPathways Senescence and Autophagy in Cancer
Mismatch repair
DNA Replication
G1 to S cell cycle control
EGF/EGFR Signaling Pathway
S Phase
Nifedipine Activity
Primary Focal Segmental Glomerulosclerosis FSGS
Retinoblastoma (RB) in Cancer
Integrated Pancreatic Cancer Pathway
Nucleotide Excision Repair
Telomere Maintenance
Synthesis of DNA
Mitotic G1-G1/S phases
Cell Cycle
Base Excision Repair
References
Ref 547217Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014130)
Ref 525924J Med Chem. 2000 Nov 30;43(24):4606-16.Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.
Ref 526389J Med Chem. 2002 Aug 1;45(16):3381-93.Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.
Ref 526489Bioorg Med Chem Lett. 2003 Jan 20;13(2):217-22.4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
Ref 526504J Med Chem. 2003 Jan 16;46(2):222-36.Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.
Ref 526991Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles.
Ref 527129J Med Chem. 2004 Jul 15;47(15):3710-22.N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 530612Eur J Med Chem. 2010 Mar;45(3):1158-66. Epub 2009 Dec 21.Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors.
Ref 551239Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010).

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