Efficacy Of Inhibitor On Wild-Type Acvr1 And R206H Mutant In C2C12 Cells (By Dla)

There are concerns that compounds that are effective in inhibiting ALK2 by occupying its ATP-binding pocket might have reduced efficacy against mutant ALK2. That will be undesirable since the compounds should also target the mutant gain-of-function ALK2 in DIPG cells. The following experiment takes advantage of the fact that ALK2-R206H mutant confers a neofunction of being activated by Activin A (not activating towards wild-type ALK2). Therefore, using Activin A as the stimulation ligand, the effectiveness of inhibition on ALK2-R206H can be specifically determined. BMP6 which activates both wild-type ALK2 and ALK2-R206H is also included.学界存在如下顾虑：通过占据活化素受体样激酶2（ALK2）的ATP结合口袋（ATP-binding pocket）以有效抑制ALK2活性的化合物，其针对突变型ALK2的抑酶活性可能会下降。这一情况并不理想，因为这类化合物还应当靶向弥漫内生型桥脑胶质瘤（diffuse intrinsic pontine glioma，DIPG）细胞中携带功能获得性（gain-of-function）突变的ALK2。后续实验利用了ALK2-R206H突变体的特性：该突变赋予ALK2新功能表型，可被活化素A（Activin A）激活，而野生型ALK2不会被活化素A激活。因此，以活化素A作为刺激配体，可特异性检测化合物对ALK2-R206H突变体的抑制效果。实验同时纳入了可同时激活野生型ALK2与ALK2-R206H突变体的骨形态发生蛋白6（bone morphogenetic protein 6，BMP6）。