Development of UPR-Targeted Treatment for Cisplatin-Induced Ototoxicity. - ABSTRACT: The overall goal of Jacaranda Biosciences, Inc. (JBI) is to develop compounds that will treat a
broad range of hearing loss indications. In this targeted SBIR project, we propose to generate, test and optimize
a series of novel JBI compounds that function through the unfolded protein response (UPR) to prevent the
ototoxicity and hearing loss caused by Cisplatin treatment. In Phase 2 of our work, relying on proof-of-concept
obtained in this initial phase, we plan to engage in a lead optimization effort to ultimately ready our team for a
first in human hearing loss (HL) treatment trial through this UPR molecular pathway.
Significance: Cisplatin, while a widely-used and highly effective chemotherapeutic, it has a major dose-limiting
side effect of ototoxicity, with nearly all cisplatin recipients having significant hearing loss.
Innovation: Through our recent and novel work in genetic and noise-induced hearing loss animal models we
discovered that homeostatic regulation of the UPR in the cochlea is a key way to prevent over-activation of the
UPR and subsequent hair cell death and hearing loss. Further detailed work has shown that eif2B activators can
specifically prevent hair cell death and hearing loss in both noise-induced and genetic HL models. We have also
generated exciting and compelling data that cisplatin ototoxicity can be treated through the same eif2B activator
arm of the UPR. To take advantage of these insights, we will optimize JBI synthesized eiF2B activators to
address UPR overactivation to treat cisplatin ototoxicity.
Aim 1. Optimize the efficacy and physicochemical properties of our IP-protected, novel eiF2B activators.
To achieve this we will fine-tune our medicinal chemistry winnowing strategy using structure-based, rational drug
design to enable us to build a range of compounds that will not only show model based effectiveness, but also
generate compounds that have superior in vitro absorption, distribution, metabolism and excretion (ADME)
properties along with rodent-based intraperitoneal (IP) pharmacokinetics.
Aim 2. Test whether optimized eiF2B activators from Aim 1 can show a reduction in deleterious side-effects
seen in the eiF2B toolkit compound ISRIB. We will also select from amongst our well-designed novel compounds
those that lessen apoptosis and UPR over-activation in our in vitro cisplatin toxicity models.
Aim 3. Test whether the candidate compounds optimized by in vitro chemistry and reduced toxicity in Aims #1
and #2 will show effectiveness in our in vivo assays, both selecting those that show reduced hair cell /cisplatin
ototoxicity along with loss in cochlear explants and also demonstrate effectiveness in protecting auditory
brainstem response (ABR) thresholds.
Summary: By the completion of Phase 1, we will have identified compounds with pre-clinical in vivo efficacy
from which we can advance to the next steps of drug development (Phase 2), including lead optimization,
entailing a more fully investigated PK, pharmacodynamics, and detailed toxicology properties.
