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

Jesse Dangerfield; Aaron DeBono; Andrew N. Keller; Tracy M. Josephs; David M. Shackleford; Karen J. Gregory; Katie Leach; Ben Capuano

doi:10.1016/j.apsb.2025.07.044

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

Jesse Dangerfield, Aaron DeBono, Andrew N. Keller, Tracy M. Josephs, David M. Shackleford, Karen J. Gregory, Katie Leach, Ben Capuano

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	5387-5399
Number of pages	13
Journal	Acta Pharmaceutica Sinica B
Volume	15
Issue number	10
DOIs	https://doi.org/10.1016/j.apsb.2025.07.044
Publication status	Published - Oct 2025

Keywords

Autosomal dominant hypocalcemia
Calcilytic
Calcium-sensing receptor
Chemoreactive
Irreversible

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10.1016/j.apsb.2025.07.044Licence: CC BY

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@article{3e54115d58fb47df8456ecaae51601c9,

title = "A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia",

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 {\textquoteleft}first-in-class{\textquoteright} chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.",

keywords = "Autosomal dominant hypocalcemia, Calcilytic, Calcium-sensing receptor, Chemoreactive, Irreversible",

author = "Jesse Dangerfield and Aaron DeBono and Keller, \{Andrew N.\} and Josephs, \{Tracy M.\} and Shackleford, \{David M.\} and Gregory, \{Karen J.\} and Katie Leach and Ben Capuano",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = oct,

doi = "10.1016/j.apsb.2025.07.044",

language = "English",

volume = "15",

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T1 - A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia

AU - Dangerfield, Jesse

AU - DeBono, Aaron

AU - Keller, Andrew N.

AU - Josephs, Tracy M.

AU - Shackleford, David M.

AU - Gregory, Karen J.

AU - Leach, Katie

AU - Capuano, Ben

PY - 2025/10

Y1 - 2025/10

N2 - 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.

AB - 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.

KW - Autosomal dominant hypocalcemia

KW - Calcilytic

KW - Calcium-sensing receptor

KW - Chemoreactive

KW - Irreversible

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U2 - 10.1016/j.apsb.2025.07.044

DO - 10.1016/j.apsb.2025.07.044

M3 - Article

AN - SCOPUS:105013564499

SN - 2211-3835

VL - 15

SP - 5387

EP - 5399

JO - Acta Pharmaceutica Sinica B

JF - Acta Pharmaceutica Sinica B

IS - 10

ER -

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

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Keywords

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A personalised pharmacogenomic approach to inform autosomal dominant hypocalcaemia treatment

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

Abstract

Keywords

Access to Document

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A personalised pharmacogenomic approach to inform autosomal dominant hypocalcaemia treatment

ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

Towards the rational design of calcium sensing receptor allosteric modulators for the treatment of osteoporosis and calcium handling disorders

Cite this