BMP Inhibitors to Treat Fibrodysplasia Ossificans Progressiva

异位骨化是指在骨骼肌和其他结缔组织中形成异位骨，是导致关节僵硬和疼痛的重要原因。进行性骨化性纤维发育不良(FOP)是一种罕见的HO，是一种常染色体显性遗传特征，通常与编码BMP I型受体ALK2的基因ACVR1的激活突变有关。FOP患者出生时只有轻微的骨骼异常，但广泛的HO几乎影响到所有的骨骼肌、韧带和筋膜，出生后由创伤或炎症引发。目前对FOP患者尚无有效的治疗方法，疾病进展导致关节功能严重受限和过早死亡。 2008年，主要合作者发现了第一个BMP信号的小分子抑制剂。这种名为多索吗啡的化合物通过抑制BMP I型受体来阻断BMP信号。通过初步的药物化学优化，开发出多索吗啡的衍生物。这项研究的总体目标是推进多索吗啡衍生物的开发，为FOP患者的临床测试做准备。 TRND的研究人员确定，最初的铅分子不适合进一步的临床前开发。因此，TRND的科学家正在进行药物化学优化，以确定一种适合正式临床前开发的化合物。

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 are performing medicinal chemistry optimization to identify a compound suitable for formal preclinical development.