Hsp90 inhibitorChemicals ResearchUpdated on Jun 29, 2018 View more like this | Visit SHIRLEY, NY | Contact BOCSCI INC |
HSP90 client proteins include steroid hormone receptors, receptor tyrosine kinases, cytosolic signaling proteins, and cell cycle regulators, some of which are involved in apoptosis and cell cycle regulation. Many Hsp90-dependent client proteins (e.g. ErbB2, B-Raf, Akt, steroid hormone receptors, mutant p53, HIF-1, survivin, telomerase, etc.) are associated with the six hallmarks of cancer. Therefore, oncogenic client protein degradation via Hsp90 inhibition represents a promising approach toward anticancer drug development.
To overcome the toxicities and poor solubilities of past HSP90 inhibitors, numerous inhibitors have since been developed which are non-ansamycin based and display less toxicity. A number of ansamycin derivatives, gamitrinibs, have been designed to accumulate in the mitochondria. The rationale for these drugs is that current HSP90 inhibitors do not reach a pool of HSP90 in the mitochondria of tumor cells. These protected proteins can still function to promote cancer cell growth. Gamitrinibs have been shown to be well tolerated and less toxic in vivo compared to previous HSP90 inhibitors. It is interesting to note that HSP90 is heavily acetylated and that HSP90 hyperacetylation can inhibit its chaperone function. In addition, HSP90 is heavily phosphorylated. It is not known if such post-translational modifications of HSP90 can be therapeutic targets.
To overcome the toxicities and poor solubilities of past HSP90 inhibitors, numerous inhibitors have since been developed which are non-ansamycin based and display less toxicity. A number of ansamycin derivatives, gamitrinibs, have been designed to accumulate in the mitochondria. The rationale for these drugs is that current HSP90 inhibitors do not reach a pool of HSP90 in the mitochondria of tumor cells. These protected proteins can still function to promote cancer cell growth. Gamitrinibs have been shown to be well tolerated and less toxic in vivo compared to previous HSP90 inhibitors. It is interesting to note that HSP90 is heavily acetylated and that HSP90 hyperacetylation can inhibit its chaperone function. In addition, HSP90 is heavily phosphorylated. It is not known if such post-translational modifications of HSP90 can be therapeutic targets.
