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BMP Inhibitors to Treat Fibrodysplasia Ossificans Progressiva

BMP 抑制剂治疗进行性骨化性纤维发育不良

基本信息

批准号：
10469236
负责人：
Philip Sanderson
金额：
$ 107.1万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469236
关键词：
ACVR1 gene Advanced Development Affect Birth Bone Growth Bone Morphogenetic Proteins Connective Tissue Development Disease Disease Progression Fascia Goals Heterotopic Ossification In Vitro Individual Inflammation Inherited Joints Lead Ligaments Measures Morbidity - disease rate Muscle Mutation Oral Osteogenesis Pain Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Premature Mortality Preparation Property Research Research Personnel Scientist Signaling Protein Skeletal Muscle Specificity Testing Therapeutics for Rare and Neglected Diseases Traumatic injury United States Food and Drug Administration autosomal dominant trait bone bone morphogenetic protein receptor type I candidate selection clinical development effective therapy efficacy evaluation in vivo inhibitor/antagonist joint function lead optimization preclinical development progressive myositis ossificans research clinical testing skeletal abnormality small molecule inhibitor

项目摘要

Heterotopic ossification (HO), the formation of ectopic bone in skeletal muscle and other connective tissues, is an important cause of morbidity from joint immobility and pain. Fibrodysplasia Ossificans Progressiva (FOP), a rare form of HO, is inherited as an autosomal dominant trait and is typically associated with activating mutations in Acvr1, the gene encoding the BMP type I receptor, ALK2. Individuals with FOP only have minimal skeletal abnormalities at birth, but extensive HO affecting nearly all skeletal muscles, ligaments and fascia is triggered after birth by traumatic injury or inflammation. No effective treatments currently exist for FOP patients, and disease progression results in severe restriction of joint function and premature mortality. In 2008, the principal collaborators identified the first small molecule inhibitor of BMP signaling. The compound, dorsomorphin, blocks BMP signaling by inhibiting BMP type I receptors. Dorsomorphin derivatives were developed through initial medicinal chemistry optimization. The overall objective of this research is to advance the development of a dorsomorphin derivative in preparation for clinical testing in patients with FOP. The TRND researchers determined that the initial lead molecule was unsuitable for further preclinical development. As such, TRND scientists performed medicinal chemistry optimization, synthesizing and evaluating with the collaborator over 1000 compounds in vitro. Activities in the lead optimization and development candidate selection included measuring compound efficacy against BMP signaling, assessing specificity and drug-like properties in vitro, and evaluating efficacy and tolerability in vivo. This led to the identification of a compound which has entered clinical development and completed phase I.

异位骨化（HO）是骨骼肌和其他结缔组织中异位骨的形成，是关节不动和疼痛的重要原因。进行性骨化性纤维发育不良（FOP）是HO的一种罕见形式，作为常染色体显性遗传性状遗传，通常与编码BMP I型受体ALK 2的基因Acvr 1的激活突变相关。患有FOP的个体在出生时仅具有最小的骨骼异常，但是在出生后由创伤性损伤或炎症触发了影响几乎所有骨骼肌、韧带和筋膜的广泛HO。FOP患者目前没有有效的治疗方法，疾病进展导致关节功能严重受限和过早死亡。 2008年，主要合作者鉴定了第一个BMP信号传导的小分子抑制剂。这种化合物dorsomorphin通过抑制BMP I型受体阻断BMP信号传导。Dorsomorphin衍生物是通过最初的药物化学优化开发的。本研究的总体目标是推进dorsomorphin衍生物的开发，为FOP患者的临床试验做准备。 TRND研究人员确定，最初的先导分子不适合进一步的临床前开发。因此，TRND科学家进行了药物化学优化，与合作者在体外合成和评估了1000多种化合物。先导物优化和开发候选物选择的活动包括测量化合物对BMP信号传导的功效，评估体外特异性和药物样性质，以及评估体内功效和耐受性。这导致鉴定出一种已进入临床开发并完成I期的化合物。