ABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) is a common (prevalence 30–70%) and potentially dose-
limiting side effect of many cancer chemotherapy drug treatment regimens. Clinically, CIPN presents with pain
that is burning, shooting or electric-shock-like. The increase in prevalence of cancer coupled with an increase in
the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large, unmet medical
problem. Neurotoxic chemotherapeutic agents (e.g., antimicrotubule agents like paclitaxel) may cause structural
damage to peripheral nerves, resulting in aberrant somatosensory processing in the peripheral and/or central
nervous system. Dorsal root ganglia (DRG) sensory neurons as well as neuronal cells in the spinal cord are the
preferential sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes
alterations in ion channels. Paclitaxel (Taxol®) increases T-type (Cav3.2) voltage-gated Ca2+ currents in rat
dorsal root ganglion (DRG) neurons; these neurons are responsible for conveying noxious sensory stimuli,
suggesting these channels are important mediators of specific sensory abnormalities associated with CIPN.
Given the roles of these channels in regulating afferent fiber excitability and synaptic function in the spinal dorsal
horn and their dynamic regulation during pain states, blocking or depleting Cav3.2 channels in these tissues
should mediate analgesic effects. In the past 5 years, considerable effort has been applied towards identifying
novel classes of T-type calcium channel blockers. This proposal aims to develop potent, orally available, and
selective Cav3.2 channel antagonists, building on the structure of a natural product – betulinic acid (BA) –
identified by the laboratory of Dr. Leslie Gunatilaka (Director, Natural Products Center, University of Arizona
(UA)) and characterized by the PI Dr. Rajesh Khanna (UA) to be Cav3.2-selective and antinociceptive in CIPN.
For this work, we have partnered with Regulonix, LLC for characterizing select Cav3.2-targeted compounds
and their analogs in in vitro and in vivo efficacy assays as well as early ADME and PK optimization. The work
proposed here is the first step in developing non-opioid pain treatments for CIPN that also curb opioid misuse
and addiction. We anticipate success against paclitaxel-induced chronic pain to translate into other chronic pain
types as well, but CIPN provides focus for early stage proof-of-concept. Regulonix’s specific aims are: (1)
Design and synthesis (Dr. L. Gunatilaka) of BA analogues and elucidation of Cav3.2 specificity and biophysical
properties of select BA analogs to gain mechanistic and safety information and to document the unique pathway
for function in neurons; (2) Profile BA analogues for their in vitro cellular cytotoxicity, early ADME and
pharmacokinetic properties, and screening for off-target effects on GPCRs, ion channels and alternative known
pain targets, including opioid receptors; and (3) Characterize the best two BA analogs, from Aim 2, for preclinical
studies using a neuropathic pain model (paclitaxel) to provide information about oral efficacy, safety, and opioid-
sparing. Upon completion, we expect to have a validated BA analog and several worthy backup compounds.
