Heat-shock protein (Hsp) inhibitors
Hsps play key roles in maintaining correctly folded conformations of multiple signalling proteins. Hsp90 inhibitors, including the ansamycins, geldanamycin and its derivatives 17-allylamino 17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), all target multiple pathways that selectively maintain the malignant phenotype. This may be because of preferential degradation of mutant oncoproteins following Hsp90 inhibition and the increased dependence of malignant cells on key Hsp90-dependent survival-signalling proteins compared to non-malignant cells.
Ansamycins destabilize signalling proteins critical to CLL cell survival, including Lyn, ZAP-70 and AKT. 17-DMAG destabilizes Ikk in vitro, thus decreasing active NF-κB and transcription of its pro-survival target genes. 17-DMAG also prolonged survival in a TCL1A-severe combined immunodeficiency transplant model of CLL. Interestingly, geldanamycin upregulated pro-apoptotic wild-type TP53 (p53) while destabilizing mutant oncogenic TP53.
Ansamycins kill CLL cells in synergy with chlorambucil, fludarabine or rituximab, preferentially induce CLL apoptosis relative to normal lymphocytes or CD34+ bone marrow progenitors and kill CLL cells regardless of prognostic criteria. In clinical trials in solid tumour patients 17-AAG was well tolerated and showed significant antitumour activity. The favourable indications resulting from in vitro and animal model studies and the ability of ansamycins to target multiple anti-apoptotic proteins in CLL suggest that these agents may be ideal candidates for novel therapeutic approaches.
2-phenylacetylenesulfonamide (PAS) is an inhibitor of the Hsp70 chaperone protein. PAS kills CLL cells at concentrations that are non-toxic to CD34+ stem cells. The CLL cell killing was at least partially dependent on the induction of the Noxa pro-apoptotic protein in response to accumulation of unfolded proteins.