ABSTRACT
The management of chronic pain is clinically challenging, and relies heavily on opioid drugs like morphine
and oxycodone. However, opioids are plagued by numerous side effects that impact quality of life, like tolerance,
constipation, and reward/addiction, contributing to an opioid abuse, addiction, and overdose crisis. These clinical
and social challenges highlight the vast medical need for new approaches to pain management. To this end, we
have pioneered an investigation into the role of Heat shock protein 90 (Hsp90) in regulating opioid signal
transduction, anti-nociception, and side effects. We have found that Hsp90 regulates mu opioid receptor (MOR)
signal transduction to different effect in brain vs. spinal cord. In brain, Hsp90 promotes MOR signaling and anti-
nociception, so that Hsp90 inhibition in brain blocks opioid anti-nociception. In spinal cord, Hsp90 blocks MOR
signaling and anti-nociception, so that Hsp90 inhibition in spinal cord enhances opioid anti-nociception. In further
studies, we found that Hsp90 inhibition in spinal cord increases morphine anti-nociceptive potency 2-3 fold
in acute and chronic pain, reduces tolerance and rescues established tolerance, all without altering the
potency of constipation and reward. These results suggest that spinal Hsp90 inhibition could be used as an
opioid dose-reduction strategy, to improve or maintain analgesic efficacy while reducing side effects. However,
one challenge to this approach is our finding that non-selective Hsp90 inhibitors, when given systemically, gave
results similar to the brain, blocking opioid anti-nociception. Seeking a way around this limitation, we found that
Hsp90 isoforms differ between brain and spinal cord, with Hsp90a alone acting in brain while Hsp90a, Hsp90ß,
and Grp94 all act in spinal cord. Hypothesizing that an isoform-selective Hsp90 inhibitor could be used to target
spinal cord-specific isoforms, we found that the Hsp90ß-selective inhibitor KUNB106 enhanced morphine anti-
nociception while rescuing established morphine tolerance when given systemically. These results strongly
suggest that Hsp90ß-selective inhibitors could be used as a novel, first-in-class opioid dose-reduction therapy.
However, KUNB106 is a first generation compound, with poor solubility and pharmacokinetics (PK) and an
uncertain therapeutic profile. In this proposal, we will thus optimize KUNB106 to create a new therapeutic to
enhance opioid therapy and reduce opioid side effects like reward/addiction. In Aim 1 we will utilize cutting edge
medicinal chemistry approaches using Hsp90 isoform co-crystallized structures to create optimized compounds
based on the KUNB106 scaffold. In Aim 2, we will test these compounds for Hsp90 isoform selectivity, ADMET
parameters, off-target interactions, and in vivo PK in mice, aiming to identify highly selective, soluble, and orally
bioavailable compounds. In Aim 3, we will test the best of these compounds for their efficacy in enhancing opioid
anti-nociception in acute and chronic pain models in mice, while reducing tolerance, constipation, reward, and
respiratory depression. Top candidates will be tested for off-target side effects and toxicity. Through this project,
we aim to create optimized candidates for further development as new therapeutics for patient pain management.