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Embargoed until 2018-11-30
Copyright: Koay, Yen Chin
Embargoed until 2018-11-30
Copyright: Koay, Yen Chin
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Abstract
This thesis describes C-terminal heat shock protein 90 (Hsp90) modulators as
potential anticancer agents. The McAlpine lab developed two molecules SM145 and
SM122, which both bind between the N and middle domain of Hsp90 and allosterically
modulate the C-terminus. SM145 and SM122 disrupt Hsp90's protein folding function as
well as the interactions between co-chaperones and the C-terminus of Hsp90. Unlike
current Hsp90 inhibitors, these molecules also inhibit Hsp90 without inducing the
problematic cell rescue response.
Chapter 2 describes the synthesis and structure-activity relationship (SAR) studies
of SM145. Two new Hsp90 inhibitors were identified during these studies: 12 and 23,
where both of these compounds contained a single thiazolyl side chain. The author
designed and synthesized these molecules, and they were made using a method that allowed
them to be produced in significantly improved yields over SM145. They also had much
greater solubility, and approximately 2-fold greater potency than SM145. Mechanistic
studies of these derivatives have validated Hsp90 as a potential target. Both 12 and 23
effectively suppressed Hsp90's function by disrupting the C-terminus chaperone function
without inducing the cell rescue response.
Chapter 3 describes the synthesis of five derivatives where an N-methylation scan
was performed at a different position around the 23 backbone. Backbone N-methylation
was also undertaken on seven other derivatives that also incorporated two thiazolyl
moieties, versus 23, which only has one thiazolyl moiety. N-methylation introduced a
conformational impact on cyclic peptides, and impacted cytotoxicity.
Chapter 4 describes the tumor selectivity between two classes of Hsp90 inhibitors,
N-terminal inhibitor (AUY922) and C-terminal modulators (12 and 23) in cancer versus
normal cells. Comparison of both inhibitor classes revealed that 12 and 23 bound
preferentially to Hsp90 from tumor cells, selectively induce apoptosis and client protein
degradation that are associated with Hsp90 inhibition in cancer cells versus normal cells,
while AUY922 failed to demonstrate differential selectivity for cancer over normal cells.
Chapter 5 describes the synthesis and Hsp90 inhibitory effect of SM-based dimeric
inhibitors of Hsp90. The results revealed that the dimerized molecules are more effective
than the monomeric inhibitor for inhibiting the binding interactions between Hsp90 and it s
co-chaperones.