Heat-shock proteins (HSPs), also called stress proteins, are a group of proteins that are present in all cells. They are induced when a cell undergoes various types of environmental stresses such as heat, cold, and oxygen deprivation. HSPs are also present in cells under normal conditions. They act like “chaperones,” regulating the folding and degradation of key signaling molecules in cells. HSPs are also believed to play a role in the presentation of peptides or antigens on the cell surface to help the immune system recognize diseased cells. One particular HSP, HSP90, has emerged as an important drug target for anticancer agents because it functions as a chaperone of oncogenic proteins, which are critical to the proliferation and survival of tumor cells. As a result, HSP90-directed drugs have the potential to inhibit the growth of a wide range of cancer cells in both solid tumors and blood-based cancers.
Mechanism Of Action
Disruption of the function of HSP90 by HSP inhibitors reduces the stability of the chronic myelogenous leukemia oncogenic protein BCR-ABL and facilitates its proteosome-mediated degradation. This degradation, in turn, lowers BCR-ABL levels and induces apoptosis and differentiation of BCR-ABL-positive leukemia cells.
Note: at the time of composing this reference, this drug has become classified under orphan drug status.
17-AAG (17-allylaminogeldanamycin) is a semisynthetic derivative of gel-danamycin and a polyketide inhibitor of HSP90 under development by Kosan Biosciences in collaboration with the National Cancer Institute (NCI) and the U.K. Institute of Cancer Research. The compound is in Phase II development as a monotherapy for melanoma and in Phase lb development as a combination therapy with imatinib for chronic myelogenous leukemia. KOS-953 is a 17-AAG variant in development by Kosan that replaces the dimethyl sulfoxide (DMSO)-egg lecithin vehicle
used in the original formulation; the aim is to improve patient tolerability and provide greater stability. This molecule is in Phase I development for multiple myeloma. An organic, solvent-free formulation of 17-AAG, CNF-1010, is being developed for the treatment of various cancers by Conforma. In October 2004, Kosan Biosciences’ 17-AAG was granted orphan drug status for the treatment of multiple myeloma and chronic myelogenous leukemia. 17-AAG is not orally bioavailable; thus, the Institute of Cancer Research is also investigating orally bioavailable analogues (Phase I) in collaboration with RiboTargets.
17-AAG is an ansamycin antibiotic that binds with high affinity into the ATP binding pocket in HSP90, inhibiting its function and inducing the degradation of the BCR-ABL oncoprotein that requires this chaperone for conformational maturation.
Investigators presented preclinical data on 17-AAG at the 44th ASH meeting in 2002. The data demonstrated that the combination of 17-AAG and imatinib in chronic myelogenous leukemia cells is synergistic in imatinib-resistant cells, including K562, EM-3, LAMA-84, and BV173 cells. The same combination also demonstrates synergy in imatinib-naive chronic myelogenous leukemia cells. Similar data were also presented in December 2004 at the 46th ASH meeting.
Another preclinical study showed that Pgp activity was increased in imatinib-resistant cells. Monotherapy with 17-AAG decreased Pgp activity in a dose-dependent fashion. The synergistic effect of both drugs in imatinib-resistant cells may thus be explained by increased intracellular levels of imatinib following 17-AAG treatment.