Inhibitor SourceBook™ Second Edition

Cyclin-Dependent Kinase (Cdk) Inhibitors
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. Eleven
members of the Cdk family are reported so far, and each
member of the family has a specific function in cellcycle.
Several Cdks, mainly Cdk2, Cdk4, and Cdk6, work
cooperatively to drive cells from G 1 phase into S phase.
Cdk4 and Cdk6 are involved in early G 1 phase, whereas
Cdk2 is required to complete G 1 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 G 1 /S transition stage. A-type cyclins,
cyclin A1 and A2, play a role during S phase. Cdk2/cyclin
A complex appears during 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 G 2
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 G 1 checkpoint
into S phase are called G 1 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
Cyclin B
Cdk1
Cdk1
Cyclin B
Cyclin A
Cdk1
Calbiochem • Inhibitor SourceBook
H
E2F
E2F
Cdk2
E2F
Cyclin A
Cdk4
Cyclin D
Cdk2
Phosphorylation/Dephosphorylation
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 G 1 /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.
Cyclin E
References:
Sridhar, J. et al. 2006. AAPS J. 8, E204.
Murray, A.W. 2004. Cell 116, 22 .
Fischer, P.M., et al. 2003. Prog. Cell Cycle Res. 5, 235.
Dai, Y., and Grant, S. 2003. Curr. Opin. Pharmacol. 3, 362.
Harper, J.W., and Adams, P.D. 200 . Chem. Rev. 101, 25 .
Ekholm, S.V., and Reed, S.I. 2000. Curr. Opin. Cell Biol. 12, 676.
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