Cancer Chemotherapy, Theoretical Foundations of
185
Target
protein
Target
protein
E3 ligase
K
K
NH2
HN
Ub
Degradation
Ub
Proteasome
E1 activating
E2 activating
Fig. 7
The proteasome in protein degradation. Target proteins for degradation are
ubiquitinated (Ub) at lysine (K) residues through a process involving a
ubiquitin-activating enzyme (E1), the transfer of ubiquitin to a conjugating enzyme
(E2), which is then transferred to a target protein by an E3 protein ligase.
Polyubiquitinated proteins are then recognized and degraded by the 26S proteasome.
Both Gleevec and Valcade directed against
the
bcr-
abl
tyrosine
kinase
and
the
proteasome respectively have shown clini-
cal efFcacy. While we await further clinical
results with Iressa, HDAC, Cdk, and
Hsp90 inhibitor programs, we are left
with the compelling view that improved
therapies will also arise from these routes
of enquiry.
Perhaps, it will be of greater signiFcance
to understand the clinical practice with
these new cancer agents. Should these
compounds be progressed as single agents
or, which seems more likely, be applied as
combination therapies perhaps with exist-
ing cytotoxic agents? It remains a signiF-
cant hurdle to address this question, and to
further provide scientiFc rationale in con-
sidering the array of possible combination
options that could be studied. An inter-
related question concerns the scheduling
regime for administering the drug, par-
ticularly in combination therapies, which
will reflect knowledge of the critical targets
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