Optimizing Small Molecule Mechanomimetics to Treat Age-related Osteoporosis.

Oak Ridge Therapeutic Discovery (Orrxd), Llc, Memphis TN

Investigators

Abstract

Abstract There is an unmet need to develop treatments for senile osteoporosis, a disorder characterized by an age-related reciprocal decrease in osteogenesis and increase in bone marrow fat. Senile osteoporosis resembles disuse osteopenia, suggesting its pathogenesis involves impaired bone mechanosensing. We discovered that the polycystin heterotrimeric complex (1PC1+3PC2) functions as a mechanosensor in osteoblasts in bone. Genetic ablation of PC1 and its downstream effector TAZ in osteoblasts results in defective osteoblast-mediated bone formation and increased bone marrow adipogenesis. Our premise is that the 1PC1+3PC2 complex in bone is a novel target for developing anabolic drugs to treat senile osteoporosis. Oak Ridge Therapeutic Discovery, LLC (ORRxD) is a drug discovery company focused on supercomputer driven structure-based small molecule hit discovery. Using structure-based drug design and extensive structure-activity relationship studies, we discovered a series of small lead molecules or “mechanomimetics” that bind to the coiled-coiled domain of 1PC1+3PC2 and selectively promote PC/1PC2 interactions to enhance calcium channel activity and TAZ signaling. These lead compounds stimulate osteoblast function and inhibit adipogenesis in vitro and stimulate osteoblast-mediated bone formation and inhibit bone marrow fat accumulation in vivo leading to increased bone mass. Patent protection for these molecules is being pursued by our academic partner, the University of Tennessee Research Foundation (UTRF). Our goal is to de-risk these novel chemical mechanomimetics. For Aim 1 we will scale up sufficient quantities to perform target binding assays, assess off-target effects, test their efficacy (EC50) to stimulate PC1/PC2 complex signaling in vitro and perform in vitro absorption, distribution, metabolism, and excretion (ADME), and in vitro toxicity studies. For Aim 2 we will perform in vivo maximum tolerated dose (MTD), pharmacokinetics (PK) and short-term efficacy studies in relevant pre-clinical mouse models. Our expected outcomes are to identify the single best compound meeting efficacy, ADME, PK, and safety properties to enter IND enabling studies in Phase II. ORRxD has the option to license these mechanomimetics from UTRF and will pursue a plan to commercialize these first-in-class drugs to treat senile osteoporosis in humans.