Personalised medicines for familial hypercalcemia and hyperparathyroidism

in Journal of Molecular Endocrinology
Authors:
Tracy Maree Josephs Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

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Frankie Zhang Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

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Le Vi Dinh Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

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Andrew N Keller Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

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Arthur D Conigrave School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia

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Ben Capuano Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

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Karen Joan Gregory Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

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Katie Leach Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

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https://orcid.org/0000-0002-9280-1803

Correspondence should be addressed to K Leach: katie.leach@monash.edu
DOI:
https://doi.org/10.1530/JME-21-0263
Volume/Issue:
Volume 69: Issue 1
Article Type:
Research Article
Page Range:
243–257
Online Publication Date:
09 May 2022
Copyright:
© Society for Endocrinology 2022
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Loss-of-function calcium-sensing receptor (CASR) mutations cause mineral metabolism disorders, familial hypocalciuric hypercalcemia, or neonatal severe hyperparathyroidism and increase the risk of femoral fracture, chronic kidney disease, coronary heart disease, and other diseases. In severe cases, CaSR mutations are lethal. Off-label use of the CaSR-positive allosteric modulator (PAM), cinacalcet, corrects hypercalcemia in some patients with CaSR mutations. However, other patients remain unresponsive to cinacalcet, attesting to the need for novel treatments. Here, we compared the effects of cinacalcet to two other clinically approved synthetic CaSR activators, evocalcet and etelcalcetide, as well as a novel PAM, 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (MIPS-VD-836-108) on clinically relevant CaSR mutations. We assessed the compounds in CaSR-expressing HEK293 cells for correction of mutation-induced impairments in intracellular calcium (Ca2+i) mobilization and cell surface expression. While cinacalcet, MIPS-VD-836-108 and evocalcet rescued the signaling of cell surface-expressed mutants, albeit to varying degrees, etelcalcetide was ineffective. Cinacalcet and evocalcet, but not MIPS-VD-836-108 or etelcalcetide, restored the expression of a R680H mutant. However, no compound rescued expression of I81K and C582R mutants or a receptor missing 77 amino acids in the extracellular domain mimicking deletion of CASRexon 5, which impairs CaSR function. These data suggest specific compounds may be clinically effective in some patients with CaSR mutations, but other patients will remain refractory to treatment with currently available CaSR-targeting activators, highlighting the need for new generation drugs to rescue both the signaling and expression of mutant CaSRs.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© Society for Endocrinology 2022
Page(s):
15
Article Type:
Research Article
Received Date:
11 Mar 2022
Accepted Date:
23 Mar 2022
Print Publication Date:
01 Jul 2022
Online Publication Date:
09 May 2022
Keywords:
calcium-sensing receptor; familial hypocalciuric hypercalcemia; neonatal severe hyperparathyroidism; positive allosteric modulators; mutations; receptor expression; receptor signaling

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