Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism

Karen Gregory, Irina Kufareva, Andrew N. Keller, Elham Khajehali, Hee-chang Mun, Mahvash Ayesha Goolam, Rebecca S Mason, Ben Capuano, Arthur Conigrave, Arthur Christopoulos, Katie Leach

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.
Original languageEnglish
Pages (from-to)96-109
Number of pages14
JournalACS Pharmacology and Translational Sciences
Volume1
Issue number2
DOIs
Publication statusPublished - 12 Sep 2018

Keywords

  • Calcium-sensing receptor
  • calhex231
  • Allosteric modulator

Cite this

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title = "Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism",
abstract = "Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.",
keywords = "Calcium-sensing receptor, calhex231, Allosteric modulator",
author = "Karen Gregory and Irina Kufareva and Keller, {Andrew N.} and Elham Khajehali and Hee-chang Mun and Goolam, {Mahvash Ayesha} and Mason, {Rebecca S} and Ben Capuano and Arthur Conigrave and Arthur Christopoulos and Katie Leach",
year = "2018",
month = "9",
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doi = "10.1021/acsptsci.8b00021",
language = "English",
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journal = "ACS Pharmacology and Translational Sciences",
issn = "2575-9108",
publisher = "American Chemical Society",
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Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism. / Gregory, Karen; Kufareva, Irina; Keller, Andrew N.; Khajehali, Elham; Mun, Hee-chang; Goolam, Mahvash Ayesha; Mason, Rebecca S; Capuano, Ben; Conigrave, Arthur; Christopoulos, Arthur; Leach, Katie.

In: ACS Pharmacology and Translational Sciences, Vol. 1, No. 2, 12.09.2018, p. 96-109.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism

AU - Gregory, Karen

AU - Kufareva, Irina

AU - Keller, Andrew N.

AU - Khajehali, Elham

AU - Mun, Hee-chang

AU - Goolam, Mahvash Ayesha

AU - Mason, Rebecca S

AU - Capuano, Ben

AU - Conigrave, Arthur

AU - Christopoulos, Arthur

AU - Leach, Katie

PY - 2018/9/12

Y1 - 2018/9/12

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AB - Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.

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