Title : Turning problems into opportunities via small molecule design
Abstract:
The Hsp90 protein folding machinery is a powerful modulator of proteostasis. It’s role in the maturation of signaling proteins and mutant proteins is well-documented and supports tumor initiation, progression and metastasis. Such studies led to the clinical evaluation of more than 20 investigational new drugs (IND) for the treatment of various cancers. Unfortunately, those studies led to the failure of most candidates due to dose-escalating toxicities that produced cardio- and ocular toxicities amongst other adverse events. Since Hsp90 exists as four isoforms and they share greater than 85% identity within the ligand binding site, those IND’s led to pan-inhibition of all four isoforms, which was the cause for most failures. While researchers stated that isoform-selective inhibition of Hsp90 was impossible, we discovered methods to inhibit each isoform with excellent selectivity. These new isoform-selective inhibitors provide significant advantages over the pan-Hsp90 inhibitors and exhibit the ability to treat cancer, glaucoma, neurological and/or metabolic disorders by targeting individual isoforms without such detriments. In contrast to the N-terminal ligand binding pocket, an allosteric binding site exists at the C-terminus and modulates Hsp90’s ATPase activity/client maturation.
Although Novobiocin was originally discovered to bind this region with poor affinity, we have optimized such analogs and revealed two classes of Hsp90 modulators that allosterically regulate protein folding. In fact, one such analog stimulates Hsp90 folding and drives induction of the heat shock response (HSR). The HSR is a pro-survival response to cellular stress and results in the induction of a large number of heat shock proteins to refold the proteins that denatured during the cellular insult. In fact, stimulation of Hsp90 activity and induction of the HSR provides an opportunity to treat a number of neurodegenerative diseases, including Alzheimer’s and neuropathy. Consequently, a novobiocin analog (cemdomespib) was rationally designed and manifested excellent biological activities that led to its Phase II investigation for the treatment of diabetic peripheral neuropathy (DPN). The design of such inhibitors and their translational development will be described in this presentation.
