Alternative approaches to Hsp90 modulation for the treatment of cancer

Abstract

Hsp90 is responsible for the conformational maturation of newly synthesized polypeptides (client proteins) and the re-maturation of denatured proteins via the Hsp90 chaperone cycle. Inhibition of the Hsp90 N-terminus has emerged as a clinically relevant strategy for anticancer chemotherapeutics due to the involvement of clients in a variety of oncogenic pathways. Several immunophilins, co-chaperones and partner proteins are also necessary for Hsp90 chaperoning activity. Alternative strategies to inhibit Hsp90 function include disruption of the C-terminal dimerization domain and the Hsp90 heteroprotein complex. C-terminal inhibitors and Hsp90 co-chaperone disruptors prevent cancer cell proliferation similar to N-terminal inhibitors and destabilize client proteins without induction of heat shock proteins. Herein, current Hsp90 inhibitors, the chaperone cycle, and regulation of this cycle will be discussed.

Figure 1. The Hsp90 chaperone cycle

The two closed conformations of Hsp90 are highlighted in the figure. The first closed conformation is stabilized by Aha1. p23 then displaces Aha1, to form the second closed conformation.

Figure 2

Celastrol and gedunin.

Figure 3

Allosteric modulators of the Hsp90 chaperone cycle.

Figure 4. N-terminal inhibitors of Hsp90

(A) Geldanamycin and derivatives, (B) radicicol and derivatives, as well as (C) Pu-3 and purine-containing analogs.

Figure 5. Isoform selective inhibitors of Hsp90

Structures of (A) Hsp90α/β inhibitor, (B) resorcinol-containing Grp94 inhibitor and (C) purine-containing Grp94 inhibitor.

Figure 6. Effect of nucleotide binding to N-terminus on C-terminal dimerization

The percentages under each Hsp90 dimer reflect the likelihood of the C-terminus being either opened or closed.

Figure 7

C-terminal inhibitors of Hsp90.