Target Validation Information
TTD ID	T85799
Target Name	Cyclin-dependent kinase 4 (CDK4)
Type of Target	Successful
Drug Potency against Target	AT7519	Drug Info	IC50 < 100 nM	[7]
	Flavopiridol	Drug Info	IC50 = 20~40 nM	[7]
	P276-00	Drug Info	IC50 = 63 nM	[7]
	Palbociclib	Drug Info	IC50 = 11 nM	[7]
	R-roscovitine	Drug Info	IC50 = 1~3 nM	[7]
	R547	Drug Info	IC50 = 1~3 nM	[7]
	SNS-032	Drug Info	IC50 = 925 nM	[7]
	ZK 304709	Drug Info	IC50 = 61 nM	[7]
	AG-024322	Drug Info	IC50 = 1~3 nM	[7]
	1-(1H-Indazol-6-yl)-3-pyridin-2-yl-urea	Drug Info	IC50 = 670 nM	[2]
	1-(7-Hydroxy-naphthalen-1-yl)-3-pyridin-2-yl-urea	Drug Info	IC50 = 7600 nM	[2]
	1-(9-Oxo-9H-fluoren-4-yl)-3-pyridin-2-yl-urea	Drug Info	IC50 = 100 nM	[2]
	1-Pyridin-2-yl-3-quinolin-5-yl-urea	Drug Info	IC50 = 2400 nM	[2]
	10-hydroxy-18-methoxybetaenone	Drug Info	IC50 = 11500 nM	[1]
	4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	Drug Info	IC50 = 13500 nM	[5]
	N-(2-(1H-Indol-3-yl)ethyl)biphenyl-4-carboxamide	Drug Info	IC50 = 16000 nM	[6]
	NU-6102	Drug Info	IC50 = 1600 nM	[4]
	PYRAZOLOPYRIDAZINE 1	Drug Info	Ki = 60 nM	[3]
	PYRAZOLOPYRIDAZINE 2	Drug Info	Ki = 190 nM	[3]
Action against Disease Model	R547	Drug Info	Induced G1-G2 arrest and apoptosis in t uMour cell lines independently of RB1 or p53 status (IC50 < 0.60 mM); induced significant t uMour growth reduction in h uMan t uMour xenografts and efficacious with daily oral dosing and weekly intravenous dosing. Early clinical trials established tolerable dosage (155 mg per m2 infusion on day 1 and day 8 during a 21-day cycle), related toxicities (nausea, emesis and hypotension) and confirmed antit uMor activity.	[7]
References
REF 1	Anthraquinones and betaenone derivatives from the sponge-associated fungus Microsphaeropsis species: novel inhibitors of protein kinases. J Nat Prod. 2000 Jun;63(6):739-45.
REF 2	Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J Med Chem. 2001 Dec 20;44(26):4615-27.
REF 3	N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular effi... J Med Chem. 2004 Sep 9;47(19):4716-30.
REF 4	Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. J Med Chem. 2006 Sep 7;49(18):5470-7.
REF 5	4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.
REF 6	Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4. Bioorg Med Chem. 2008 Aug 15;16(16):7728-39.
REF 7	Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.

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