Abstract: It has been discovered that the cyclic peptide EnnA inactivates the Hsp90 chaperone pathway, but without activating an extensive heat shock response and overexpression of anti-apoptotic proteins. Mechanistically distinct, EnnA inhibits Hsp90 and destabilize PDL-1 and IDO, two major immune checkpoints mediating tumor-induced immune suppression. The provided herein show that EnnA profoundly modulates the cytokine signature of cancer cells and promotes a cytokine profile that favors an immune attack on tumor cells. This translates into highly efficacious anti-tumor activity in vivo, which, when combined with a single dose of chemotherapy, completely reduced the tumor burden in experimental animals and instilled highly efficient immune memory against the primary tumor.

Abstract: It has been discovered that the cyclic peptide EnnA inactivates the Hsp90 chaperone pathway, but without activating an extensive heat shock response and overexpression of anti-apoptotic proteins. Mechanistically distinct, EnnA inhibits Hsp90 and destabilize PDL-1 and IDO, two major immune checkpoints mediating tumor-induced immune suppression. The provided herein show that EnnA profoundly modulates the cytokine signature of cancer cells and promotes a cytokine profile that favors an immune attack on tumor cells. This translates into highly efficacious anti-tumor activity in vivo, which, when combined with a single dose of chemotherapy, completely reduced the tumor burden in experimental animals and instilled highly efficient immune memory against the primary tumor.

Abstract: It has been discovered that the cyclic peptide EnnA inactivates the Hsp90 chaperone pathway, but without activating an extensive heat shock response and overexpression of anti-apoptotic proteins. Mechanistically distinct, EnnA inhibits Hsp90 and destabilize PDL-1 and IDO, two major immune checkpoints mediating tumor-induced immune suppression. The provided herein show that EnnA profoundly modulates the cytokine signature of cancer cells and promotes a cytokine profile that favors an immune attack on tumor cells. This translates into highly efficacious anti-tumor activity in vivo, which, when combined with a single dose of chemotherapy, completely reduced the tumor burden in experimental animals and instilled highly efficient immune memory against the primary tumor.

Abstract: Pharmaceutical compositions including an effective amount of a capsaicin and inhibitors of Hsp90 to decrease or inhibit Hsp70 and Hsp90 chaperone pathways in cells are disclosed. Methods of inhibiting the Hsp70 and Hsp90 chaperone pathways including contacting cells expressing the Hsp70/Hsp90 complex with an effective amount of a capsaicin in combination with inhibitors of Hsp90 to decrease or inhibit the Hsp70 and Hsp90 chaperone pathways are provided. The methods can reduce the viability of target cells, for example, by increasing apoptosis or pro-apoptotic pathways. In preferred embodiments, the methods reduce or do not increase Hsp70, Hsp90, Hsp40, or HOP expression; reduce or do not increase heat shock response; reduce or do not increase pro-survival pathways in cells. Methods of treating cancer and other diseases using the disclosed compositions and methods are provided.

Abstract: Methods of inhibiting the Hsp90 chaperone pathway including contacting one or more target cells with an effective amount of a naturally occurring beauvericin, a synthetic beauvericin, or a derivative, analog or prodrug, or a pharmacologically active salt thereof to reduce, decrease, or inhibit the Hsp90 chaperone pathway in the cells compared to a control are disclosed. The methods can reduce the viability of the target cells, for example, by increasing apoptosis or pro-apoptotic pathways. In preferred embodiments, the methods reduce or do not increase Hsp70, Hsp24, Hsp40, or HOP expression; reduce or do not increase the heat shock response; reduce or do not increase pro-survival pathways in the cells. Methods of treating diseases such as cancer, inflammatory diseases or disorders, neurodegenerative diseases, and infectious diseases using the disclosed compositions and methods are also disclosed.