# A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia

## TL;DR

A new chemoreactive drug for treating autosomal dominant hypocalcemia shows prolonged effects by binding irreversibly to a key calcium receptor.

## Contribution

A first-in-class chemoreactive calcilytic with irreversible receptor binding and sustained PTH release is introduced.

## Key findings

- The chemoreactive NAM ATF936-NCS binds irreversibly to the calcium-sensing receptor.
- It stimulates prolonged parathyroid hormone release in vivo, offering therapeutic potential for ADH.
- This compound provides a new chemical probe for developing longer-acting treatments for ADH.

## Abstract

Autosomal dominant hypocalcemia (ADH) type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants. The calcium-sensing receptor (CaSR) is a class C GPCR that responds to elevated extracellular calcium (Ca2+o) by inhibiting parathyroid hormone (PTH) secretion and promoting renal excretion of Ca2+ and other salts to restore physiologically normal Ca2+o concentrations. CaSR negative allosteric modulators (NAMs) transiently raise PTH levels in individuals with ADH1, restoring Ca2+o concentration to a physiological normal range. Herein we disclose the discovery of a chemoreactive NAM (ATF936-NCS, 4) for the CaSR that (i) is wash-resistant indicative of irreversible receptor binding and (ii) stimulates prolonged PTH release in vivo. This ‘first-in-class’ chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.

The discovery of a first-in-class chemoreactive CaSR NAM derived from ATF936 that demonstrates a unique receptor binding mechanism and a sustained PTH release profile of therapeutic potential.Image 1