Transcript CDK2−Cyclin A2 Inhibitory Activities of Analogues

H. Lee Moffitt Cancer Center and Research Institute
2013. 06. 14
Lee,Sang-Hwi
1) http://www.youtube.com/watch?v=UE7pCF8EV9o
2) http://www.youtube.com/watch?v=tsc1LZKRWAY
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a family of serine/threonine kinases involved in cell cycle progression and transcription.
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Cyclin-dependent kinase 2 (CDK2)
G1 checkpoint를 지나서 DNA 복제, G2 checkpoint를 지나서 유사분열을 하기 위해서는 CDK 단백질의 활성이 필요
CDK는 단독으로 활성을 가질 수 없으며 Cyclin이라는 단백질과 결합되어 kinase 활성을 갖게 된다.
Cyclin-CDK complex는 세포증식에 관련된 단백질들을 인산화켜서 세포 분열을 유도한다
유사분열이 완료되거나 DNA 복제가 완료되면 더 이상의 kinase 활성이 필요치 않으므로 Cyclin-CDK complex의 Cyclin이
분해되어 CDK의 활성이 사라진다.
• 유사분열시에 세포분열이 완료되면 Ubiquitin 단백질이 MPF의 cyclin에 결합하여 cyclin 단백질을 분해한다
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CDK2−Cyclin A2 Inhibitory Activities of Analogues
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CDK2−Cyclin A2 Inhibitory Activities of Analogues
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Crystallography of representative CDK2-inhibitor complex
potential π bonding interaction
hinge region (residues 81-84), gatekeeper (Phe80 residue), the DFG motif (residues 145-147), other residues
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CDK Selectivity / Antiproliferative activity
(phase III)
Rb deficient cell line : BT-549, MDA-MB-468
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0.39 μM
0.011 μM
0.41 μM
0.27 μM
To evaluate if the antiproliferative activity of 51 is caused by inhibition of cellular CDK2,
we selected inhibition of Rb phosphorylation at the CDK-specific sites Ser807/811 and activation of caspase-3 at the
onset of apoptosis as mechanism-based markers for CDK-specific inhibitors
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339 panel kinases % inhibition
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