# Design of Calcium-sensing Receptor Targeted Thera(g)nostic Agents

> **NIH NIH R41** · INLIGHTA BIOSCIENCES, LLC · 2024 · $323,743

## Abstract

Summary
Calcium-sensing receptor (CaSR), as one of the family C G-protein-coupled receptors (GPCRs), largely
modulates extracellular Ca2+ by triggering multiple intracellular signaling pathways. CaSR is expressed in the
kidneys, parathyroid glands, colon, and other cells, representing its differential yet key roles in responding to
extracellular calcium, amino acids, and metabolites, in different organs. Numerous diseases have been attributed
to calcium mishandling (e.g.,nephrolithiasis) and secondary hyperparathyroidism (HPT), with over 200 CaSR
mutations that can significantly alter CaSR expression. There is a pressing unmet medical need to develop
positive allosteric modulators for PKD and other diseases with cellular and organ specificity and reduced liver
toxicity. The major barriers to developing effective drugs are a lack of knowledge of tempo-spatial quantitative
expression of CaSR in the body and its changes during disease progression and regression. We recently
determined the first crystal structure of the human CaSR extracellular domain (ECD) with a bound tryptophan
derivative (TNCA) at 2.1 Å, a potential positive allosteric modulator. This led us to design and synthesize a drug
candidate TNCA that has strong agonist activity and specificity to CaSR. The goal of this Phase I proposal is to
acquire proof-of-concept results for design and generation of TNCA analogs having optimal drug activity and
cellular specificity as agonists and antagonists. In addition, we will also develop CaSR targeted PET agents for
renal imaging in a preclinical Pkhd1PCK rat model (studies in this model led to clinical trials of an FDA-approved
PKD therapeutic). Aim 1 is to optimize and determine TNCA analogs with best CaSR drug activity as agonists &
antagonists. Aim 2 is to perform in vivo mapping of CaSR distribution in PKD (Pkhd1PCK) rat model by microPET
imaging. Phase II will further validate drug efficacy of TNCA analogs, imaging capability for CaSR associated
kidney diseases using animal models, and safety profile for an eIND. Success in our proposed studies will
provide essential results for a novel avenue in the development of CaSR specific drug candidates for the effective
treatment of various CaSR associated human diseases using newly available structures and patented
methodology. In addition, the developed PET imaging agents will enable us to map CaSR distribution and
heterogeneous expression during PKD disease progression and regression in vivo, as a companion diagnostic
for patient risk stratification, and for outcome prediction and novel drug development. We anticipate that the
proposed studies will foster the development of transformative novel markers of the disease activity that will
enhance clinical care of PKD and other kidney diseases.

## Key facts

- **NIH application ID:** 11006566
- **Project number:** 1R41DK139927-01A1
- **Recipient organization:** INLIGHTA BIOSCIENCES, LLC
- **Principal Investigator:** Mark Myron Goodman
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $323,743
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006566

## Citation

> US National Institutes of Health, RePORTER application 11006566, Design of Calcium-sensing Receptor Targeted Thera(g)nostic Agents (1R41DK139927-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11006566. Licensed CC0.

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