Allosteric modulators of the PTH/PTHrP receptor

Veterans Health Administration, Decatur PA

Investigators

Abstract

Summary Disturbances in the maintenance of normal mineral-ion and vitamin D (VitD) balance result in kidney stones, and osteoporosis and lead to significant and costly pathologies affecting Veterans’ health. To overcome limitations of teriparatide (PTH1-34) efficacy in the treatment of osteoporosis, this project proposes to test and optimize in silico identified small non-peptidic molecules (referred to as Pitt molecules) that can act as allosteric modulators of parathyroid hormone type 1 receptor (PTH1R) signaling as future potential therapeutic candidates for osteo- porosis and hyperparathyroidism. An interdisciplinary approach has been developed to demonstrate the efficacy of Pitt molecules in modulating PTH signaling in vitro, and thereby identify small molecules with therapeutic potential against bone and ion mineral diseases. The specific Aims of this project are: (1) Small molecule selection. We will characterize pharmacological pro- files of a series of 22 non-peptidic allosteric modulators in cultured cells expressing the PTH1R to identify the most effective allosteric small molecules for modulating PTH1R signaling using state-of-the-art optical analysis of receptor signaling in live cells. The most efficient compounds will be optimized to achieve higher affinity and efficacy via medicinal chemistry methods. (2) Small molecule validation. The most effective positive and neg- ative allosteric modulators will be validated by testing their effects on osteoblast via PTHR signaling and miner- alization. (3) Chemical optimization of small molecules efficacy. Advanced organic chemistry methods will be applied to refine and optimize the efficacy and potency of selected allosteric modulators of PTH1R function. The significance of this research program lies in its premise to lay the groundwork for a future translational research program that examines the therapeutic utility of these Pitt molecules for treatment of osteoporosis.