Very compelling scientific evidence suggests that the HER2-amplified subtype of breast cancer can be eradicated in patients through treatments that inactivate HER2 function. However all HER2-targeting drugs developed to date have shown only incremental activities. Recent evidence from our group reveals that this is due to the unexpectedly resilient nature of the functionally relevant HER2-HER3 tumor driver, and a robust signal buffering capacity that protects it against a nearly two log inhibition by drugs. These data highlight the need for next-generation approaches that are much more potent than kinase inhibitors or antibody therapeutics to successfully inactivate HER2-HER3 signaling. Here we propose such a concept.
We believe that the HER2-HER3 driver can be inactivated in patients through the development of a new class of agents that inhibit Hsp90 in a client-selective manner. Our concept derives from the fact that HER2 and HER3 are highly dependent on the molecular chaperone Hsp90 for stability and expression, and are unusually and exquisitely sensitive to drugs that inhibit Hsp90 function. However inhibiting Hsp90 function potentially affects the expression and function of all its clients, significantly limiting the clinical potential of this treatment approach. We propose to develop a new class of client-selective Hsp90 inhibitors.
Current Hsp90 inhibitors bind within the ATP pocket of Hsp90, inhibiting its ATPase cycle and producing a total loss-of-function that affects all its protein clients. Recent structure-function work by our group and others suggests that different clients bind Hsp90 through different modes of contact and likely involve different cochaperones. Therefore, small molecule inhibitors acting at specific allosteric sites within Hsp90 are likely to affect its interaction in a much more client-selective fashion. Indeed, we have recently discovered a prototype for such a compound, although one that spares HER2. We now seek to identify candidate Hsp90 allosteric site inhibitors that more selectively degrade HER2-HER3 signaling. Such allosterically acting compounds will then be screened for HER2-HER3 inhibiting activity in breast cancer cell based assays. These studies will lay the groundwork for a next-generation class of compounds that we believe will finally provide the potency required to inactivate the highly resilient HER2-HER3 tumor driver.
In this pilot project we will develop FRET-based probes that can be used in high throughput screens of Hsp90 inhibitors. A dye will be ligated to each arm of a recombinant human Hsp90 dimer. One assay will employ a pair of FRET dyes located proximally, and another assay will employ a pair of FRET dyes located more distally. The two probe sets will allow us to more fully interrogate the conformational landscape of Hsp90. This pilot award will enable us to begin developing and testing the assay while larger applications are being submitted to fund the actual drug development effort.