Personalised medicines for familial hypercalcemia and hyperparathyroidism

in Journal of Molecular Endocrinology
View More View Less
  • 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  • | 2 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  • | 3 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  • | 4 School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia
  • | 5 Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

Correspondence should be addressed to K Leach: katie.leach@monash.edu
Restricted access

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.

 

Society for Endocrinology logo

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 427 427 427
Full Text Views 21 21 21
PDF Downloads 27 27 27
  • Ahmad N, Bahasan M, Al-Ghamdi BAA, Al-Enizi HF & Al-Zahrani AS 2017 Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation. Clinical Cases in Mineral and Bone Metabolism 14 354358. (https://doi.org/10.11138/ccmbm/2017.14.3.354)

    • Search Google Scholar
    • Export Citation
  • Alexander ST, Hunter T, Walter S, Dong J, Maclean D, Baruch A, Subramanian R & Tomlinson JE 2015 Critical cysteine residues in both the calcium-sensing receptor and the allosteric activator AMG 416 underlie the mechanism of action. Molecular Pharmacology 88 853865. (https://doi.org/10.1124/mol.115.098392)

    • Search Google Scholar
    • Export Citation
  • Alon US & VandeVoorde RG 2010 Beneficial effect of cinacalcet in a child with familial hypocalciuric hypercalcemia. Pediatric Nephrology 25 17471750. (https://doi.org/10.1007/s00467-010-1547-5)

    • Search Google Scholar
    • Export Citation
  • Atay Z, Bereket A, Haliloglu B, Abali S, Ozdogan T, Altuncu E, Canaff L, Vilaca T, Wong BY & Cole DE et al.2014 Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet. Bone 64 102107. (https://doi.org/10.1016/j.bone.2014.04.010)

    • Search Google Scholar
    • Export Citation
  • Babinsky VN, Hannan FM, Gorvin CM, Howles SA, Nesbit MA, Rust N, Hanyaloglu AC, Hu J, Spiegel AM & Thakker RV 2016 Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein alpha-11 mutations causing hypercalcemic and hypocalcemic disorders. Journal of Biological Chemistry 291 1087610885. (https://doi.org/10.1074/jbc.M115.696401)

    • Search Google Scholar
    • Export Citation
  • Beerepoot P, Nazari R & Salahpour A 2017 Pharmacological chaperone approaches for rescuing GPCR mutants: current state, challenges, and screening strategies. Pharmacological Research 117 242251. (https://doi.org/10.1016/j.phrs.2016.12.036)

    • Search Google Scholar
    • Export Citation
  • Brown EM 2013 Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Practice and Research: Clinical Endocrinology and Metabolism 27 333343. (https://doi.org/10.1016/j.beem.2013.02.006)

    • Search Google Scholar
    • Export Citation
  • Capozza M, Chinellato I, Guarnieri V, Di Lorgi N, Accadia M, Traggiai C, Mattioli G, Di Mauro A & Laforgia N 2018 Case report: Acute clinical presentation and neonatal management of primary hyperparathyroidism due to a novel CaSR mutation. BMC Pediatrics 18 340. (https://doi.org/10.1186/s12887-018-1319-0)

    • Search Google Scholar
    • Export Citation
  • Chang W, Chen TH, Pratt S & Shoback D 2000 Amino acids in the second and third intracellular loops of the parathyroid Ca2+-sensing receptor mediate efficient coupling to phospholipase C. Journal of Biological Chemistry 275 1995519963. (https://doi.org/10.1074/jbc.M909613199)

    • Search Google Scholar
    • Export Citation
  • Chen P, Sohn W, Narayanan A, Gisleskog PO & Melhem M 2019 Bridging adults and paediatrics with secondary hyperparathyroidism receiving haemodialysis: a pharmacokinetic-pharmacodynamic analysis of cinacalcet. British Journal of Clinical Pharmacology 85 13121325. (https://doi.org/10.1111/bcp.13900)

    • Search Google Scholar
    • Export Citation
  • Christopoulos A 1998 Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. Trends in Pharmacological Sciences 19 351357. (https://doi.org/10.1016/s0165-6147(9801240-1)

    • Search Google Scholar
    • Export Citation
  • Cook AE, Mistry SN, Gregory KJ, Furness SG, Sexton PM, Scammells PJ, Conigrave AD, Christopoulos A & Leach K 2015 Biased allosteric modulation at the CaSR engendered by structurally diverse calcimimetics. British Journal of Pharmacology 172 185200. (https://doi.org/10.1111/bph.12937)

    • Search Google Scholar
    • Export Citation
  • Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM & Christopoulos A 2012 Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153 12321241. (https://doi.org/10.1210/en.2011-1426)

    • Search Google Scholar
    • Export Citation
  • Dershem R, Gorvin CM, Metpally RPR, Krishnamurthy S, Smelser DT, Hannan FM, Carey DJ, Thakker RV, Breitwieser GE & Regeneron Genetics Center 2020 Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population. American Journal of Human Genetics 106 734747. (https://doi.org/10.1016/j.ajhg.2020.04.006)

    • Search Google Scholar
    • Export Citation
  • Diepenhorst NA, Leach K, Keller AN, Rueda P, Cook AE, Pierce TL, Nowell C, Pastoureau P, Sabatini M & Summers RJ et al.2018 Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. British Journal of Pharmacology 175 40954108. (https://doi.org/10.1111/bph.14344)

    • Search Google Scholar
    • Export Citation
  • Dinh LV, DeBono A, Keller AN, Josephs TM, Gregory KJ, Leach K & Capuano B 2021 Development of AC265347-inspired calcium-sensing receptor ago-positive allosteric modulators. ChemMedChem 16 34513462. (https://doi.org/10.1002/cmdc.202100368)

    • Search Google Scholar
    • Export Citation
  • Fisher MM, Cabrera SM & Imel EA 2015 Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients. Endocrinology, Diabetes and Metabolism Case Reports 2015 150040. (https://doi.org/10.1530/EDM-15-0040)

    • Search Google Scholar
    • Export Citation
  • Forman TE, Niemi AK, Prahalad P, Shi RZ & Nally LM 2019 Cinacalcet therapy in an infant with an R185Q calcium-sensing receptor mutation causing hyperparathyroidism: a case report and review of the literature. Journal of Pediatric Endocrinology and Metabolism 32 305310. (https://doi.org/10.1515/jpem-2018-0307)

    • Search Google Scholar
    • Export Citation
  • Gannon AW, Monk HM & Levine MA 2014 Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. Journal of Clinical Endocrinology and Metabolism 99 711. (https://doi.org/10.1210/jc.2013-2834)

    • Search Google Scholar
    • Export Citation
  • Gao Y, Robertson MJ, Rahman SN, Seven AB, Zhang C, Meyerowitz JG, Panova O, Hannan FM, Thakker RV & Brauner-Osborne H et al.2021 Asymmetric activation of the calcium-sensing receptor homodimer. Nature 595 455459. (https://doi.org/10.1038/s41586-021-03691-0)

    • Search Google Scholar
    • Export Citation
  • Garcia Soblechero E, Ferrer Castillo MT, Jimenez Crespo B, Dominguez Quintero ML & Gonzalez Fuentes C 2013 Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. Neonatology 104 104108. (https://doi.org/10.1159/000350540)

    • Search Google Scholar
    • Export Citation
  • Garcia-Nafria J, Lee Y, Bai X, Carpenter B & Tate CG 2018 Cryo-EM structure of the adenosine A2a receptor coupled to an engineered heterotrimeric G protein. eLife 7 e35946. (https://doi.org/10.7554/eLife.35946)

    • Search Google Scholar
    • Export Citation
  • Goolam MA, Ward JH, Avlani VA, Leach K, Christopoulos A & Conigrave AD 2014 Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor. FEBS Letters 588 33403346. (https://doi.org/10.1016/j.febslet.2014.07.022)

    • Search Google Scholar
    • Export Citation
  • Gorvin CM 2019 Molecular and clinical insights from studies of calcium-sensing receptor mutations. Journal of Molecular Endocrinology 63 R1R16. (https://doi.org/10.1530/JME-19-0104)

    • Search Google Scholar
    • Export Citation
  • Gorvin CM, Hannan FM, Cranston T, Valta H, Makitie O, Schalin-Jantti C & Thakker RV 2018 Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function Galpha11 mutation. Journal of Bone and Mineral Research 33 3241. (https://doi.org/10.1002/jbmr.3241)

    • Search Google Scholar
    • Export Citation
  • Gregory KJ, Giraldo J, Diao J, Christopoulos A & Leach K 2020 Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites. Molecular Pharmacology 97 3545. (https://doi.org/10.1124/mol.119.118091)

    • Search Google Scholar
    • Export Citation
  • Gunganah K, Grossman A & Druce M 2014 Recurrent pancreatitis in a patient with familial hypocalciuric hypercalcaemia treated successfully with cinacalcet. Endocrinology, Diabetes and Metabolism Case Reports 2014 140050. (https://doi.org/10.1530/EDM-14-0050)

    • Search Google Scholar
    • Export Citation
  • Hannan FM, Babinsky VN & Thakker RV 2016 Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. Journal of Molecular Endocrinology 57 R127R142. (https://doi.org/10.1530/JME-16-0124)

    • Search Google Scholar
    • Export Citation
  • Howles SA, Hannan FM, Babinsky VN, Rogers A, Gorvin CM, Rust N, Richardson T, McKenna MJ, Nesbit MA & Thakker RV 2016 Cinacalcet for symptomatic hypercalcemia caused by AP2S1 mutations. New England Journal of Medicine 374 13961398. (https://doi.org/10.1056/NEJMc1511646)

    • Search Google Scholar
    • Export Citation
  • Kahvecioglu D, Atasay B, Berberoglu M, Yildiz D, Cakir U, Akduman H, Erdeve O, Siklar Z, Magdelaine C & Lienhardt-Roussie A et al.2014 A novel mutation in the calcium sensing receptor gene in a neonate with severe hyperparathyroidism. Genetic Counseling 25 331335.

    • Search Google Scholar
    • Export Citation
  • Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, Latorraca NR, Hilger D, Dawson R & Matile H et al.2018 Structure of the micro-opioid receptor-Gi protein complex. Nature 558 547552. (https://doi.org/10.1038/s41586-018-0219-7)

    • Search Google Scholar
    • Export Citation
  • Lam CW, Lee KF, Chan AO, Poon PM, Law TY & Tong SF 2005 Novel missense mutation in the CASR gene in a Chinese family with familial hypocalciuric hypercalcemia. Clinica Chimica Acta: International Journal of Clinical Chemistry 360 167172. (https://doi.org/10.1016/j.cccn.2005.04.026)

    • Search Google Scholar
    • Export Citation
  • Leach K, Wen A, Davey AE, Sexton PM, Conigrave AD & Christopoulos A 2012 Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. Endocrinology 153 43044316. (https://doi.org/10.1210/en.2012-1449)

    • Search Google Scholar
    • Export Citation
  • Leach K, Wen A, Cook AE, Sexton PM, Conigrave AD & Christopoulos A 2013 Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium-sensing receptor by positive and negative allosteric modulators. Endocrinology 154 11051116. (https://doi.org/10.1210/en.2012-1887)

    • Search Google Scholar
    • Export Citation
  • Leach K, Gregory KJ, Kufareva I, Khajehali E, Cook AE, Abagyan R, Conigrave AD, Sexton PM & Christopoulos A 2016 Towards a structural understanding of allosteric drugs at the human calcium sensing receptor. Cell Research 26 574592. (https://doi.org/10.1038/cr.2016.36)

    • Search Google Scholar
    • Export Citation
  • Leach K, Hannan FM, Josephs TM, Keller AN, Moller TC, Ward DT, Kallay E, Mason RS, Thakker RV & Riccardi D et al.2020 International Union of Basic and Clinical Pharmacology. CVIII. Calcium-sensing receptor nomenclature, pharmacology, and function. Pharmacological Reviews 72 558604. (https://doi.org/10.1124/pr.119.018531)

    • Search Google Scholar
    • Export Citation
  • Letz S, Elbelt U, Strasburger CJ, Haag C, Schulze E, Frank-Raue K, Raue F, Mayr B & Schofl C 2014 CaSR mutants disrupting the disulfide bond between C582 and C568 in the cysteine-rich domain of the CaSR do not act as dominant negative mutants. Experimental and Clinical Endocrinology and Diabetes 122 P038. (https://doi.org/10.1055/s-0034-1372055)

    • Search Google Scholar
    • Export Citation
  • Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G & Coudrat T et al.2017 Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546 118123. (https://doi.org/10.1038/nature22327)

    • Search Google Scholar
    • Export Citation
  • Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L, Koole C, Truong TT, Thal DM & Lei S et al.2018 Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555 121125. (https://doi.org/10.1038/nature25773)

    • Search Google Scholar
    • Export Citation
  • Ma JN, Owens M, Gustafsson M, Jensen J, Tabatabaei A, Schmelzer K, Olsson R & Burstein ES 2011 Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. Journal of Pharmacology and Experimental Therapeutics 337 275284. (https://doi.org/10.1124/jpet.110.178194)

    • Search Google Scholar
    • Export Citation
  • Mastromatteo E, Lamacchia O, Campo MR, Conserva A, Baorda F, Cinque L, Guarnieri V, Scillitani A & Cignarelli M 2014 A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria. BMC Endocrine Disorders 14 81. (https://doi.org/10.1186/1472-6823-14-81)

    • Search Google Scholar
    • Export Citation
  • Mayr B, Schnabel D, Dorr HG & Schofl C 2016 GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts. European Journal of Endocrinology 174 R189R208. (https://doi.org/10.1530/EJE-15-1028)

    • Search Google Scholar
    • Export Citation
  • Murphy H, Patrick J, Baez-Irizarry E, Lacassie Y, Gomez R, Vargas A, Barkemeyer B, Kanotra S & Zambrano RM 2016 Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: a rare cause of life-threatening hypercalcemia. European Journal of Medical Genetics 59 227231. (https://doi.org/10.1016/j.ejmg.2016.02.001)

    • Search Google Scholar
    • Export Citation
  • Nemeth EF, Van Wagenen BC & Balandrin MF 2018 Discovery and development of calcimimetic and calcilytic compounds. Progress in Medicinal Chemistry 57 186. (https://doi.org/10.1016/bs.pmch.2017.12.001)

    • Search Google Scholar
    • Export Citation
  • Oda Y, Tu CL, Pillai S & Bikle DD 1998 The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation. Journal of Biological Chemistry 273 2334423352. (https://doi.org/10.1074/jbc.273.36.23344)

    • Search Google Scholar
    • Export Citation
  • Oda Y, Tu CL, Chang W, Crumrine D, Komuves L, Mauro T, Elias PM & Bikle DD 2000 The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation. Journal of Biological Chemistry 275 11831190. (https://doi.org/10.1074/jbc.275.2.1183)

    • Search Google Scholar
    • Export Citation
  • Padhi D, Langman CB, Fathallah-Shaykh S, Warady BA, Salusky IB, Lee E, Wang C & Posvar E 2012 An open-label study to evaluate a single-dose of cinacalcet in pediatric dialysis subjects. Pediatric Nephrology 27 19531959. (https://doi.org/10.1007/s00467-012-2186-9)

    • Search Google Scholar
    • Export Citation
  • Reh CM, Hendy GN, Cole DE & Jeandron DD 2011 Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CaSR) R185Q mutation: clinical benefit from cinacalcet. Journal of Clinical Endocrinology and Metabolism 96 E707E712. (https://doi.org/10.1210/jc.2010-1306)

    • Search Google Scholar
    • Export Citation
  • Savas-Erdeve S, Sagsak E, Keskin M, Magdelaine C, Lienhardt-Roussie A, Kurnaz E, Cetinkaya S & Aycan Z 2016 Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases. Journal of Pediatric Endocrinology and Metabolism 29 11031110. (https://doi.org/10.1515/jpem-2015-0261)

    • Search Google Scholar
    • Export Citation
  • Schnabel D, Letz S, Lankes E, Mayr B & Schofl C 2014 Severe but not neonatally lethal. A homozygous inactivating CaSR mutation in a 3 year old child. Experimental and Clinical Endocrinology and Diabetes 122 P041. (https://doi.org/10.1055/s-0034-1372058)

    • Search Google Scholar
    • Export Citation
  • Sun X, Huang L, Wu J, Tao Y & Yang F 2018 Novel homozygous inactivating mutation of the calcium-sensing receptor gene in neonatal severe hyperparathyroidism responding to cinacalcet therapy: a case report and literature review. Medicine 97 e13128. (https://doi.org/10.1097/MD.0000000000013128)

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Karperien M, Hamdy NA, de Boer H & Hermus AR 2006 Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor. Journal of Internal Medicine 260 177182. (https://doi.org/10.1111/j.1365-2796.2006.01684.x)

    • Search Google Scholar
    • Export Citation
  • Tokunaga S, Endo Y & Kawata T 2019 Pharmacological and clinical profiles of a novel calcimimetic, evocalcet (ORKEDIA(R)). Nihon Yakurigaku Zasshi: Folia Pharmacologica Japonica 154 3543. (https://doi.org/10.1254/fpj.154.35)

    • Search Google Scholar
    • Export Citation
  • White E, McKenna J, Cavanaugh A & Breitwieser GE 2009 Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Molecular Endocrinology 23 11151123. (https://doi.org/10.1210/me.2009-0041)

    • Search Google Scholar
    • Export Citation
  • Wilhelm-Bals A, Parvex P, Magdelaine C & Girardin E 2012 Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 129 e812e816. (https://doi.org/10.1542/peds.2011-0128)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Sun B, Feng D, Hu H, Chu M, Qu Q, Tarrasch JT, Li S, Sun Kobilka T & Kobilka BK et al.2017 Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546 248253. (https://doi.org/10.1038/nature22394)

    • Search Google Scholar
    • Export Citation