Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies.
Among heat shock proteins the focus on HSP90 has increased due to its involvement in several cellular phenomena and more importantly in disease progression.
Proteosome analysis revealed that Hsp90 is differentially expressed between ewing’s sarcoma cell lines, sensitive and resistant to specific IGF1R/KIT inhibitors.
HSP90 inhibitor NVP-BEP800 has been described to affect stability of SRC kinases clients and growth of T-cell and B-cell acute lymphoblastic leukemias.
[10] Addition of such inhibitor causes proteosomal degradation of signaling proteins like steroid receptors, Raf kinase and Akt.
Currently, anthracyclines, cytarabine and etoposide are widely used in the treatment of AML due to their ability to induce apoptosis in leukemic cells.
The signaling pathways by which these drugs work are not completely understood, but direct effects as DNA damage, mitochondrial electron transport interference, generation of oxidizing radicals and proteasomal activation have been demonstrated or hypothesized.
The ATP antagonist GA and its derivative 17AAG blocks p23 association with Hsp90, induces proteasomal degradation of survival signaling.
In their study, Gausdal and colleagues found that anthracyclines and other chemotherapeutic drugs like cytarabine and etoposide, but not GA alone, induced caspase-dependent cleavage of p23.
Finally they concluded that Hsp90, and consequently signaling mediated by client proteins in the Hsp90 multiprotein complex, may be targeted through p23 in chemotherapy-induced cell death in AML.
Based on this information and advanced rational drug design technique, phenomenologically relevant scaffolds can be constructed.
Pimitespib is an oral small molecule inhibitor of the α and β isoforms of heat shock protein 90 (HSP90).
The good tolerability seen with the first-in-class drug 17-AAG has encouraged many biotechnology and large pharma companies to enter the field.
Following on from the initial proof of concept studies with the natural product agents, considerable progress has been made in the preclinical development of small molecule, synthetic inhibitors, as exemplified by the purine and pyrazole based compounds.
Current Medicinal Chemistry activities are focusing on the combined use of high throughput screening and structure-based design, coupled to the evaluation of the compounds in robust and mechanistically- informative biological assays.
Particular areas of interest will include the potential for orally active HSP90 inhibitors and for the development of isoform-selective drugs that are targeted to particular members of the HSP90 family (DMAG –N-OXIDE).
Furthermore, a portfolio of drugs can be envisaged that target various points in the protein quality control pathways of the malignant cell and other diseases states.