Merck UK - Calbiochem - Inhibitors: Phosphorylation/Dephosphorylation

		Technical Resources

		Technical Information

		Calbiochem Information

		Inhibitor Resource

		Phosphorylation Dephosphorylation

		AKT
		AMPK
		Aurora Kinase
		Cam Kinase
		Casein Kinase
		Checkpoint Kinase
		Cyclin-dependent Kinase
		DNA-Dependent Protein Kinase
		Glycogen Synthase Kinase
		c-Jun N-Terminal Kinase
		IP3 Kinase & TGF-b Receptor I Kinase
		MAP Kinase
		MLCK
		PI 3 Kinase
		Protein Kinase A
		Protein Kinase C
		Protein Kinase G
		Protein Phosphatase
		Protein Tyrosine Kinase
		Raf Kinase
		Rho Kinase
		Sphingosine Kinase

Phosphorylation/Dephosphorylation: Cyclin-Dependent Kinase (Cdk) Inhibitors

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Selected Cdk Inhibitors |

Inhibitors | Related Products

Cell cycle progression is regulated by a series of sequential events that include the activation and subsequent inactivation of cyclin dependent kinases (Cdks) and cyclins. Cdks are a group of serine/threonine kinases that form active heterodimeric complexes by binding to their regulatory subunits, cyclins. Several Cdks, mainly Cdk2, Cdk4, and Cdk6, work cooperatively to drive cells from G₁ phase into S phase. Cdk4 and Cdk6 are involved in early G₁ phase, whereas Cdk2 is required to complete G₁ phase and initiate S phase. Both Cdk4 and Cdk6 form active complexes with the D type of cyclins (cyclins D1, D2, and D3). Cdk2 is sequentially activated by the E type of cyclins, cyclins E1 and E2, during G₁/S transition stage. A type cyclins, cyclin A1 and A2, play a role during the S phase. Cdk2/cyclin A complex appears during the late S phase and plays a role in progression of DNA replication. The cyclins that are involved in regulating the passage of the cell from the G₂ checkpoint into M phase are known as mitotic cyclins and they associate with mitotic Cdks. Similarly, cyclins that are involved in the passage of cells from the G₁ checkpoint into S phase are called G₁ cyclins. Once the Cdks have completed their role, they undergo a rapid programmed proteolysis via ubiquitin-mediated delivery to the proteasome complex.

It is important to note here that Cdk5, a serine-threonine kinase, originally cloned from HeLa cells, is not directly involved in cell cycle. It is primarily active in neuronal tissue. Cdk5, in conjunction with its neuron-specific activator p35 (Cdk5/p35), has been implicated in tau hyperphosphorylation. Cdk5/p35 is also involved in neuronal migration and differentiation during development of the nervous system.

The enzymatic activity of a Cdk is regulated at three levels: cyclin association, subunit phosphorylation, and association with Cdk inhibitors. When cyclins initially bind to Cdks, the resulting complex is inactive. The phosphorylation of Cdks by Cdk activating kinases leads to their activation. Two main categories of Cdk inhibitors are reported in cells. They are the INK and the WAF/Kip families. The members of the INK family, INK4A (p16), INK4B (p15), INK4C (p18), and INK4D (p19), bind to Cdk4 and Cdk6 and block their interaction with D type cyclins thereby inhibiting Cdk activity. The members of the WAF/Kip family, WAF1 (p21), Kip1 (p27), and Kip2 (p57), form heterotrimeric complexes with the G₁/S Cdks. Their major action is reported to be the inhibition of the kinase activity of Cdk/cyclin E complex.

From a therapeutic standpoint Cdks are considered promising targets in cancer chemotherapy. The most promising strategies involve designing inhibitors that either block Cdk activity or prevent their interaction with cyclins. Most of the currently available molecules target the ATP-binding site of these enzymes. Such an approach might create serious problems as catalytic residues are well conserved across eukaryotic protein kinases. However, compounds such as Flavopiridol, Olomoucine, and Butyrolactone-1 that exhibit greater specificity for Cdks have shown promise.

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Table 1: Selected Cdk Inhibitors (IC₅₀ in mM)

Product	Cat. No.	Cdk1	Cdk2	Cdk4	Cdk5
Alsterpaullone	126870	0.035	-	-	-
Alsterpaullone, 2-Cyanoethyl	126871	0.000230		-	0.030
Aloisine A	128125	0.15 (B)	0.12 (A), 0.40 (E)		0.20 (p25), 0.16 (p35)
Aloisine A, RP106	128135	0.70 (B)			1.50 (p35)
Aminopurvalanol A	164640	0.033	0.033 (A), 0.028 (E)		0.020 (p35)
Bohemine	203600	1.0	0.80 (E)	-	-
Cdk Inhibitor, p35	219457	0.10	0.80 (E)	-	-
Cdk1 Inhibitor	217695	5.8	-	-	25.0
Cdk1 Inhibitor, CGP74514A	217696	0.025 (B)	-	-	-
Cdk1 Inhibitor III	217697	28.8 (B)	-	-	-
Cdk1/2 Inhibitor II, NU6102	217713	0.0095 (B)	0.0054 (A3)	1.6 (D1)	-
Cdk1/5 Inhibitor	217720	0.60 (B)	-	-	0.40 (p25)
Cdk2 Inhibitor I	219442	-	0.038^a	-	-
Cdk2 Inhibitor II	219445	0.78	0.060	-	-
Cdk2 Inhibitor III	238803	4.2 (B)	0.5 (A and E)	215.0 (D1)	-
Cdk2/5 Inhibitor	219448	-	2.0^b	-	2.0^b
Cdk4 Inhibitor	219476	2.1 (B)	0.52 (E)	0.076 (D1)	-
Cdk4 Inhibitor II, NSC 625987	219477	> 100 (A)	> 100 (E)	0.20 (D1)	-
Fascaplysin, Synthetic	341251	> 100	> 50 (A and E)	0.35 (D1)	20.0
Indirubin-3’-monoxime	402085	0.18	-	-	0.10
Indirubin-3’-monoxime, 5-Iodo-	402086	0.025	-	-	0.020
Indirubin-3’-monoxime-5-sulphonic Acid	402088	0.005	-	-	0.007
Kenpaullone	422000	0.40 (B)	0.68 (A), 7.5 (E)	-	0.85
Olomoucine	495620	7.0 (B)	7.0 (A and E)	>1000 (D)	3.0 (p35)
Olomoucine II	495621	0.02 (B)
Olomoucine, Iso	495622	> 500 (B)		> 1000 (D)	> 1000 (p35)
Oxindole I	499600	10.2	10.0 (E)	4.90
Protein Kinase inhibitor, DMAP	476493	300 (B)
Purvalanol A	540500	0.004 (B)	0.07 (A), 0.035 (E)		0.075 (p35)
Roscovitine	557360	0.65	0.7 (A and E)	>1000	0.2 (p35)
Roscovitine, (S)-Isomer	557362	0.80 (B)
Staurosporine	569397	0.009	0.007	-	-
SU9516	572650	0.04 (B)	0.022 (A)	0.20 (D1)
WHI-P180, Hydrochloride	681500		1.0