Summary Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is detected in 64% of cancer patients during all phases
of cancer. Sensory symptoms in the hands and/or feet, typically in a “stocking-glove” pattern, are common, and
manifested as pain, numbness, and/or tingling. CIPN can result in chemotherapy dose reduction or
discontinuation, and can also have long-term effects on the quality of life. The course of CIPN can be
unpredictable: while symptoms may resolve after chemotherapy is discontinued, they can also continue for
years. Since its introduction in the 1970s, the antimicrotubule Paclitaxel (Taxol®) has been used as an
effective anticancer agent against lung, breast, ovarian, leukopenia and liver cancer. But, Paclitaxel-induced
peripheral neuropathy is the major dose-limiting side effect of paclitaxel. Taxanes (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 key sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but
includes dysregulation of ion channels. For example, Paclitaxel increases expression of low-voltage activated
T-type (Cav3.2) Ca2+ channels in rat DRG neurons; these neurons are responsible for conveying noxious
sensory stimuli, suggesting these channels are important mediators of specific sensory abnormalities
associated with CIPN. T-type Ca2+ channels are critical determinants of increased neuronal excitability and
neurotransmission accompanying persistent neuropathic pain. Though Cav3.2 has been targeted clinically with
small molecule antagonists, no drugs targeting these channels have advanced to phase II human clinical trials.
This proposal aims to explore multicomponent reaction products, developed in the laboratory of the PI - Dr. Jun
Wang, for the rapid identification of potent and selective T-type Ca2+ channel antagonists. For this work, we
have partnered with Dr. Rajesh Khanna (PI and Chief Scientific Officer, Regulonix, LLC) for characterizing
select compounds and their analogs in in vitro and in vivo efficacy assays as well PK optimization. The work
proposed here is the first step in developing non-opioid pain treatments for CIPN. We anticipate success
against paclitaxel-induced chronic pain will 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 of UAWJ111
analogs and elucidation of channel specificity and biophysical properties of select UAWJs to gain mechanistic
and safety information and to document the unique pathway for function in relevant neuronal cells; (2) Profile
the in vitro cellular cytotoxicity and pharmacokinetic properties of UAWJ111 analogs; (3) Characterize the best
two UAWJs, from Aim 2, for preclinical studies using a neuropathic pain model (paclitaxel) to provide
information about efficacy. At the conclusion of our study, we expect to have a validated UAWJ analog and
several worthy backup compounds.
