Biomedical Engineering Reference
In-Depth Information
Leu 265
Pro 22
Zinc
Phe 141
His 131
His 132
(C)
FIGURE 23.6 (continued) (C) Crystal structure of SAHA complexed with HDAC-like protein. (A) Close-up
of interactions with the active site Zn 2+ and two adjacent binding histidines. (B) Hydrophobic cavity illustrated
with the protein surface added. (Computer model courtesy of Dr. S. Vadlamudi, Topotarget, U.K.)
inhibition results in the generation of hyper-acetylated histone tails. These changes in histone acety-
lation levels (and changes in histone PTMs in general) are accompanied by changes in the cellular
gene expression proi le. This is because the pattern of histone acetylation marks (and the PTM pat-
tern as a whole) at any given gene affects the transcriptional state of that gene by determining which
multiprotein complexes are recruited in its promotor region, in this way regulating the activity of
the RNA polymerase II machinery in a local fashion.
Two types of HDACs exists. One uses a coordinated zinc atom to cleave the
ε
- N lysine bound,
- N group to NAD + . Only compounds
inhibiting the activity of the zinc dependant family will be addressed here. Several structural and
chemical classes of HDAC inhibitors exist, and many are derived from or inspired from natural prod-
ucts (Figure 23.6B). The most advanced HDAC inhibitor is the hydroxamic acid Zolinza, developed
by Merck & Co, which is inspired by the natural product antifungicide HDAC inhibitor Tricostatin
A (Figure 23.6B). Zolinza comprises (1) a hydrophobic moiety designed to bind to the surface of
the zinc dependent HDACs, (2) a carbon linker designed to penetrate through a hydrophobic cav-
ity in the HDAC enzyme, at the bottom of which the coordinated zinc atom is situated, and (3) a
hydroxamic acid group at the end of the linker, designed to chelate this active site zinc atom in order
to abrogate enzymatic activity. This compound is now approved in the United States by the FDA
to treat cutaneous T-cell lymphoma (CTCL). Models of Zolinza bound to zinc-dependent HDAC
enzyme is depicted in Figure 23.6C. Another hydroxamic acid in late clinical development (phase
III) is belinostat developed by TopoTarget A/S (Figure 23.6B). Other classes of HDAC inhibitors in
clinical development is the cyclic peptide depsipeptid (Gloucester Pharmaceuticals) and the benz-
amide MS275 (Schering AG) (Figure 23.6B). Valporic acid (Figure 23.6B), a known antiepileptic,
has recently been found to have weak HDAC inhibitory activity. This compound is now in clinical
testing for the treatment of basal cell carcinoma (skin cancer) and familial adenomatous polyposis
(an intestinal predisposition to cancer) (TopoTarget A/S).
Some of the genes whose expression most consistently changes across almost all cells examined
as a consequence of HDAC inhibition is the p21 Waf1/Cip1 cyclin dependant kinase inhibitor (induced)
and various cyclines (repressed). These effects lead to arrest of the cell cycle. Interestingly, HDAC
induced cell cycle arrest is often followed by apoptosis in cancer cells while normal cells display a
while the other deacetylates histones by transferring the lysine
ε
 
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