Optimizing Small Molecule Mechanomimetics to Treat Age-related Osteoporosis.

优化小分子力学模拟治疗与年龄相关的骨质疏松症。

基本信息

批准号：
10807685
负责人：
L DARRYL QUARLES
金额：
$ 24.97万
依托单位：
OAK RIDGE THERAPEUTIC DISCOVERY (ORRXD), LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10807685
关键词：
Ablation Acute Adipose tissue Affect Age-Related Osteoporosis Binding Biological Assay Bone Formation Stimulation Bone Marrow Bone Resorption Calcium Channel Chemicals Clinical Trials Coiled-Coil Domain Complex Disease Disease model Drug Design Drug Kinetics Evaluation Excretory function Fatty acid glycerol esters Foundations Fracture Funding Future Genetic Goals Gonadal Steroid Hormones Health Care Costs Human Impairment In Vitro Intravenous Investigational Drugs Investigational New Drug Application Knockout Mice Lead Legal patent Licensing Marrow Maximum Tolerated Dose Mechanics Mediating Metabolism Microgravity Molecular Oral Osteoblasts Osteogenesis Osteopenia Outcome PKD1 gene PKD2 gene Pathogenesis Pharmaceutical Chemistry Pharmaceutical Preparations Phase Postmenopause Property Proprotein Convertase 1 Proprotein Convertase 2 Research Risk Safety Senile Osteoporosis Senility Series Signal Transduction Specificity Structure Structure-Activity Relationship Technology Transfer Tennessee Testing Therapeutic Toxic effect Universities Wild Type Mouse Woman absorption age related bone bone disuse atrophy bone mass clinical candidate commercialization drug action drug candidate drug development drug discovery efficacy study efficacy testing genetic approach hormone deficiency improved in silico in vivo in vivo Model innovation lead series lipid biosynthesis mechanotransduction meetings men mortality mouse genetics mouse model new therapeutic target novel novel drug class novel therapeutics pharmacologic phase 1 study phase 2 study pre-clinical scale up screening skeletal small molecule supercomputer targeted treatment therapeutic target therapy development

项目摘要

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.