Bone-strengthening calcitonin peptide (CHEMBL2369907)

What this is

This card represents the salmon calcitonin scaffold (CHEMBL2369907), a 32-residue peptide hormone analog used as the reference high-potency calcitonin-receptor agonist in a 2002 medicinal-chemistry study (Taylor et al., J Med Chem 2002). Salmon calcitonin itself is a hormone first isolated from the ultimobranchial gland of fish and characterized by Niall, Keutmann, Copp, and Potts (PNAS 1969); it lowers blood calcium by switching off the bone-resorbing cells called osteoclasts. The stored 30-letter raw sequence (CSNLSTCVLGKLSQELHKLQTYRTNTGSGT) is a stripped representation of the active molecule, which is a 32-residue peptide with a disulfide bond closing a ring between Cys1 and Cys7, two prolines at positions 23 and 32, and a C-terminal amide (-NH₂) — none of which are visible in the bare-letter sequence shown above. In ChEMBL the entry is encoded with D-proline at positions 23 and 32; native pharmaceutical salmon calcitonin uses L-proline at both positions (Niall et al., PNAS 1969).

History

Calcitonin as a hormone was discovered in 1962 by D. Harold Copp and B. Cheney, who isolated it from the parathyroid–thyroid region and showed it lowered blood calcium (Copp & Cheney 1962). Salmon calcitonin was sequenced shortly afterward by Niall, Keutmann, Copp, and Potts (PNAS 1969), who established that the fish hormone shares only 9 of 32 amino-acid positions with human calcitonin but binds the human receptor far more tightly — the basis for its eventual use as a pharmaceutical. The synthetic salmon form (also called salcatonin) reached clinical use in the 1970s–1980s for Paget's disease of bone and hypercalcemia, and a nasal-spray formulation (Miacalcin) was developed for postmenopausal osteoporosis. The specific molecule indexed here as CHEMBL2369907 served as the parent reference compound in a 2002 Rutgers/industry collaboration (Taylor et al., J Med Chem 2002) that explored side-chain lactam-bridged analogs to identify why salmon calcitonin is more potent than the human hormone.

What it does

Calcitonin acts at the calcitonin receptor (CALCR), a Gs-coupled GPCR expressed at high density on osteoclasts (the cells that dissolve bone) and in the kidney. When the hormone binds, the receptor triggers cAMP production and protein-kinase-A signaling, which causes osteoclasts to retract their ruffled membrane, disassemble their actin cytoskeleton, and stop resorbing bone. The result at the whole-body level is a fall in blood calcium and a slowing of skeletal turnover. Salmon calcitonin is roughly an order of magnitude more potent than the human peptide at the human calcitonin receptor — the difference traces to amino-acid substitutions in positions 10–27 that stabilize the alpha-helical mid-region of the hormone (Niall et al., PNAS 1969; Taylor et al., J Med Chem 2002).

Evidence

• In vitro: In the Taylor et al. study (J Med Chem 2002), the parent salmon calcitonin compound indexed as CHEMBL2369907 was assigned reference potency (100%) and reported a binding Ki of 0.051 nM at the human calcitonin receptor stably expressed in HEK293 cells, a functional ED50 of 0.115 nM in human-receptor cAMP signalling assays in neuroblastoma cells, and an IC50 of 0.377 nM displacing radioligand from rat-brain calcitonin receptors (data deposited in ChEMBL document CHEMBL1135734; Taylor et al., 2002). These values are the benchmark against which the lactam-bridged human calcitonin analogs in that paper were compared.
• Human: Salmon calcitonin (the pharmaceutical, salcatonin) has been used clinically for decades in Paget's disease of bone, tumor-induced hypercalcemia, and — historically — postmenopausal osteoporosis. The nasal-spray formulation for osteoporosis was the subject of a meta-analysis by the European Medicines Agency that pooled long-term placebo-controlled trials (EMA review, 2012).

Known effects

• Inhibition of osteoclast bone resorption — established mechanism via CALCR/cAMP/PKA signaling (Taylor et al. 2002; Niall et al. 1969)
• Lowering of serum calcium in hypercalcemia — clinically used; EMA-approved indication for the injectable form (EMA, 2012)
• Reduction of bone pain in Paget's disease — historical clinical observation; EMA-approved indication (EMA, 2012)

Safety signals

In July 2012 the European Medicines Agency, after reviewing pooled long-term trial data, concluded that "the risk of developing cancer was 0.7% to 2.4% higher in patients receiving calcitonin-containing medicines compared to those patients receiving placebo, with the higher rates seen in trials with intranasal calcitonin" (EMA, 20 July 2012). This finding triggered the withdrawal of the nasal-spray formulation in the EU and restrictions on the injectable form to short-term use only. A meta-analysis subsequently reviewed the data (Wells et al., Osteoporosis International 2016; DOI 10.1007/s00198-015-3339-z) but the regulatory restrictions remained in place. In the United States, an FDA Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee voted 12–9 against continued marketing of the nasal-spray formulation for osteoporosis in March 2013, citing the cancer signal and a marginal efficacy benefit.

Regulatory status

• EU: Injectable/infusion salmon calcitonin remains approved by the EMA only for (i) prevention of acute bone loss due to sudden immobilisation (maximum 4 weeks), (ii) Paget's disease in patients who do not respond to alternative treatments (normally maximum 3 months), and (iii) hypercalcaemia caused by cancer. The nasal-spray formulation was withdrawn following the EMA recommendation of 20 July 2012 (EMA, 2012).
• US: Salmon calcitonin injection (Miacalcin) remains FDA-approved for Paget's disease of bone, hypercalcemia, and postmenopausal osteoporosis. The nasal-spray formulations (Miacalcin Nasal Spray and Fortical) remain on the US market for postmenopausal osteoporosis as of the most recent FDA-advisory-committee review (2013 joint advisory committee), though that committee voted against continued marketing for that indication.

Related peptides

Salmon calcitonin belongs to the calcitonin gene-related peptide family, which also includes human calcitonin, amylin (islet amyloid polypeptide), adrenomedullin, and CGRP itself — all of which act at receptors built from CALCR or its close relative CALCRL with associated RAMP accessory proteins. The 2002 study indexed by this card (Taylor et al., J Med Chem 2002) used this scaffold as the high-potency reference against which lactam-bridged human-calcitonin analogs were benchmarked, leading the authors to propose a "new design concept" for potent calcitonin analogs based on conformational pre-organization of the receptor-binding helix.