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Optimizing Small Molecule Mechanomimetics to Treat Age-related Osteoporosis.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AG082524-01A1
Agency Tracking Number: R41AG082524
Amount: $249,658.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIA
Solicitation Number: PA22-178
Timeline
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-30
Award End Date (Contract End Date): 2024-08-31
Small Business Information
5100 POPLAR AVE STE 3122
Memphis, TN 38137-3125
United States
DUNS: 118552282
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 L QUARLES
 (901) 448-5385
 lquarle1@tennessee.edu
Business Contact
 LEIGH QUARLES
Phone: (816) 686-3240
Email: hq@orrxd.com
Research Institution
 UNIVERSITY OF TENNESSEE HEALTH SCI CTR
 
62 S DUNLAP, SUITE 300
MEMPHIS, TN 38103-4903
United States

 Nonprofit College or University
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.

* Information listed above is at the time of submission. *

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