There is an unmet need to develop treatments for senile osteoporosis, a disorder characterized by an age-relatedreciprocal decrease in osteogenesis and increase in bone marrow fat. Senile osteoporosis resembles disuseosteopenia, suggesting its pathogenesis involves impaired bone mechanosensing. We discovered that thepolycystin heterotrimeric complex (1PC1+3PC2) functions as a mechanosensor in osteoblasts in bone. Geneticablation of PC1 and its downstream effector TAZ in osteoblasts results in defective osteoblast-mediated boneformation and increased bone marrow adipogenesis. Our premise is that the 1PC1+3PC2 complex in bone is anovel 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 hitdiscovery. Using structure-based drug design and extensive structure-activity relationship studies, wediscovered a series of small lead molecules or "mechanomimetics" that bind to the coiled-coiled domain of1PC1+3PC2 and selectively promote PC/1PC2 interactions to enhance calcium channel activity and TAZsignaling. These lead compounds stimulate osteoblast function and inhibit adipogenesis in vitro and stimulateosteoblast-mediated bone formation and inhibit bone marrow fat accumulation in vivo leading to increased bonemass. Patent protection for these molecules is being pursued by our academic partner, the University ofTennessee Research Foundation (UTRF). Our goal is to de-risk these novel chemical mechanomimetics. ForAim 1 we will scale up sufficient quantities to perform target binding assays, assess off-target effects, test theirefficacy (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 maximumtolerated dose (MTD), pharmacokinetics (PK) and short-term efficacy studies in relevant pre-clinical mousemodels. Our expected outcomes are to identify the single best compound meeting efficacy, ADME, PK, andsafety properties to enter IND enabling studies in Phase II. ORRxD has the option to license thesemechanomimetics from UTRF and will pursue a plan to commercialize these first-in-class drugs to treat senileosteoporosis in humans.
Public Health Relevance Statement: This proposal is to further validate novel anabolic chemical compounds that activate the polycystins/TAZ
mechanosensing complex in bone to treat senile osteoporosis. We have discovered highly potent chemical lead
series of mechanomimetics that stimulate osteoblast-mediated bone formation and inhibit bone marrow
adipogenesis in mouse models. Proposed studies for Phase I will assess off-target effects, preform ADMET and
PK studies and confirm the efficacy of the best lead compounds in preclinically relevant disease mouse models,
to de-risk these compounds for future Investigational New Drug (IND) enabling studies in Phase II.
Project Terms: | <4-3 Hydrophobic Repeat> | | 