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的科学家们进行了药物化学优化，与合作者一起在体外合成和评估了1000多种化合物。先导优化和开发候选药物选择的活动包括测量化合物对BMP信号的有效性，在体外评估特异性和类药物特性，以及在体内评估有效性和耐受性。这导致了一种化合物的鉴定，该化合物已进入临床开发并完成了第一阶段。

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.