Optimizing Small Molecule Mechanomimetics to Treat Age-related Osteoporosis.

摘要 存在开发用于老年性骨质疏松症的治疗的未满足的需求，所述老年性骨质疏松症是一种以年龄相关的骨质疏松为特征的病症。 骨生成的相互减少和骨髓脂肪的增加。老年骨质疏松症类似废用 骨质减少，提示其发病机制涉及骨机械感知受损。我们发现 多囊蛋白异三聚体复合物（1 PC 1 + 3 PC 2）在骨骼成骨细胞中发挥力学传感器的作用。遗传 成骨细胞中PC 1及其下游效应物TAZ的消融导致成骨细胞介导的骨缺损 形成和增加骨髓脂肪生成。我们的前提是，骨中的1 PC 1 + 3 PC 2复合物是一种 为开发治疗老年性骨质疏松症的合成代谢药物提供了新的靶点。橡树岭治疗发现有限责任公司 （ORRxD）是一家专注于超级计算机驱动的基于结构的小分子药物发现公司。 的发现利用基于结构的药物设计和广泛的构效关系研究，我们 发现了一系列小的先导分子或“机械模拟物”，它们结合到 1 PC 1 + 3 PC 2和选择性地促进PC/1 PC 2相互作用以增强钙通道活性和TAZ 信号这些先导化合物在体外刺激成骨细胞功能并抑制脂肪形成， 成骨细胞介导的骨形成和抑制体内骨髓脂肪积聚，导致骨增加 马萨诸塞州这些分子的专利保护正在由我们的学术合作伙伴， 田纳西研究基金会（UTRF）。我们的目标是降低这些新型化学机械模拟物的风险。为 目标1：我们将扩大足够的数量，以进行靶向结合试验，评估脱靶效应，测试其 在体外刺激PC 1/PC 2复合物信号传导并进行体外吸收、分布 代谢和排泄（ADME）以及体外毒性研究。对于目标2，我们将进行体内最大值 相关临床前小鼠的耐受剂量（MTD）、药代动力学（PK）和短期疗效研究 模型我们的预期结果是确定满足疗效、ADME、PK和 安全特性，以进入IND II期研究。ORRxD可以选择许可这些 UTRF的mechanomimetics，并将推行一项计划，将这些一流的药物商业化，以治疗老年 人类的骨质疏松症

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.