Development of Highly Potent and Selective Diaminothiazole inhibitors of Cyclin-Depen-

dents Kinase (CDK)

2013. 06. 14Lee,Sang-Hwi

H. Lee Moffitt Cancer Center and Research Insti-tute

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1) http://www.youtube.com/watch?v=UE7pCF8EV9o

2) http://www.youtube.com/watch?v=tsc1LZKRWAY

Cyclin-dependent kinase 2 (CDK2)

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• a family of serine/threonine kinases involved in cell cycle progression and tran-scription.

• G1 checkpoint 를 지나서 DNA 복제 , G2 checkpoint 를 지나서 유사분열을 하기 위해서는 CDK 단백질의 활성이 필요• CDK 는 단독으로 활성을 가질 수 없으며 Cyclin 이라는 단백질과 결합되어 kinase 활성을 갖게 된다 .• Cyclin-CDK complex 는 세포증식에 관련된 단백질들을 인산화켜서 세포 분열을 유도한다• 유사분열이 완료되거나 DNA 복제가 완료되면 더 이상의 kinase 활성이 필요치 않으므로 Cyclin-CDK complex 의 Cy-

clin 이 분해되어 CDK 의 활성이 사라진다 . • 유사분열시에 세포분열이 완료되면 Ubiquitin 단백질이 MPF 의 cyclin 에 결합하여 cyclin 단백질을 분해한다

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CDK2−Cyclin A2 Inhibitory Activities of Ana-logues

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CDK2−Cyclin A2 Inhibitory Activities of Ana-logues

Crystallography of representative CDK2-inhibitor complex

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hinge region (residues 81-84), gatekeeper (Phe80 residue), the DFG motif (residues 145-147), other residues

potential π bonding interaction

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CDK Selectivity / Antiproliferative activity

Rb deficient cell line : BT-549, MDA-MB-468

(phase III)

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0.41 μM

0.011 μM

0.39 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

0.27 μM

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339 panel kinases % inhibition