BMP Inhibitors to Treat Fibrodysplasia Ossificans Progressiva

异位骨化（HO），即骨骼肌和其他结缔组织中异位骨的形成，是关节不活动和疼痛发病的重要原因。进行性骨化性纤维发育不良 (FOP) 是一种罕见的 HO 形式，作为常染色体显性遗传，通常与 Acvr1 的激活突变相关，Acvr1 是编码 BMP I 型受体 ALK2 的基因。 FOP 患者在出生时仅有轻微的骨骼异常，但出生后因创伤性损伤或炎症而引发广泛的 HO，影响几乎所有骨骼肌、韧带和筋膜。目前对于 FOP 患者尚无有效的治疗方法，疾病进展会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 信号传导小分子抑制剂。这种化合物，dorsomorphin，通过抑制 BMP I 型受体来阻断 BMP 信号传导。 Dorsomorphin 衍生物是通过最初的药物化学优化而开发的。这项研究的总体目标是推进 Dorsomorphin 衍生物的开发，为 FOP 患者的临床测试做好准备。 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 科学家正在进行药物化学优化，以确定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.