Parathyroid hormone (PTH) type 1 receptor (PTHR) is an indispensable G protein-coupled receptor (GPCR) of class B that functions to regulate blood levels of vitamin D, calcium, and phosphate ions in the body, as well as bone turnover. Disturbance in the maintenance of normal mineral-ion and vitamin D balance results in kidney stones and osteoporosis. PTHR hyperactivity causes endocrine diseases including primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, and Jansen’s metaphyseal chondrodysplasia, all of which are significant and costly pathologies. No pharmaceutical therapy is available for the treatment of PTHR hyperactivity, and the only bone-building agents designed to treat osteoporosis have limited efficacy, short plasma lifetimes, and require restricted usage due to the risk of developing osteosarcoma. Furthermore, these therapies need to be administered via frequent injections, limiting patient adherence. An orally-available PTHR-targeting small molecule drug is urgently needed.
Description
The allosteric drugs disclosed here were designed to specifically modulate selected interactions with the PTHR upon altering its structural mechanics. This “allo-targeting” approach is being hailed in drug discovery and development for its use in designing efficacious therapies. A structure-guided computational approach was used to identify allosteric druggable sites in PTHR and to predict compounds that would bind to this site, and Pitt researchers discovered four small-molecule compounds that act as negative allosteric modulators of PTHR signaling. Further computational protocols indicated that the experimentally-identified small molecule drug candidates were predicted to bind to this site, lending more evidence to the use of this computational approach to discovering druggable sites in other class B GPCRs.
Applications
· Developing drugs to treat hyperparathyroidism and its related pathologies, such as osteoporosis
Advantages
· Identified molecules have a unique mode of action
· Allosteric molecules modulate endogenous ligand action and have saturable effects compared to orthosteric ligands
· First integrated use of two technologies, ESSA and Pharmmaker, to predict useful compounds for notoriously difficult targets
· Possibly extendable to other GPCRs, which constitute the second largest protein drug target family
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US20240156779A1
