# Inhibition of CaVα-β interaction with orally available small organic molecules for chronic pain

> **NIH NIH R41** · REGULONIX, LLC · 2021 · $400,000

## Abstract

ABSTRACT Revisions noted in blue font
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 (small fibers), 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. For example, the taxane paclitaxel (Taxol®) increases N-type (CaV2.2)
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. CaV2.2 channels are critical determinants of increased neuronal excitability
and neurotransmission accompanying persistent neuropathic pain. Though CaV2.2 has been targeted clinically
with Prialt® and Gabapentin, both drugs are encumbered with serious side effects. This proposal aims to develop
potent, orally available, and selective CaV2.2 channel antagonists, building on the seminal discovery of a
quinazoline CaV2.2 antagonist (IPPQ) developed in the laboratory of Dr. Rajesh Khanna (University of Arizona
(UA)), as potential candidates for the management of CIPN. IPPQ represents a new class of compounds
targeting CaV2.2 via a completely unique mechanism – that of targeting the CaVα-CaVβ interface. For this work,
we have partnered with Regulonix, LLC for characterizing select CaV2.2-targeted compounds and their analogs
in in vitro and in vivo efficacy assays as well as early ADME profiling. The work proposed here is the first step in
developing non-opioid pain treatments for CIPN. 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 (Dr. Marcel Patek, Medicinal chemistry consultant, former Vice
President of Chemistry at Icagen, Inc.) and synthesis (Dr. Wei Wang, Director of the Drug Discovery Center, UA
or CROs) and optimization of drug-like lead series (IPPQ) and elucidation of channel specificity and biophysical
properties of select IPPQ analogs to gain mechanistic and safety information and to document the unique
pathway for function in relevant neuronal cells; (2) Profile IPPQ analogs for their in vitro cellular cytotoxicity,
physi...

## Key facts

- **NIH application ID:** 10267604
- **Project number:** 1R41CA257845-01A1
- **Recipient organization:** REGULONIX, LLC
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267604

## Citation

> US National Institutes of Health, RePORTER application 10267604, Inhibition of CaVα-β interaction with orally available small organic molecules for chronic pain (1R41CA257845-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10267604. Licensed CC0.

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