Heterotopic ossification (HO)， the pathological extraskeletal formation of bone， can arise from blast injuries， severe burns， orthopedic procedures and gain-of-function mutations in a component of the bone morphogenetic protein (BMP) signaling pathway， the ACVR1/ALK2 receptor serine-threonine (protein) kinase， causative of Fibrodysplasia Ossificans Progressiva (FOP). All three ALKs (-2， -3， -6) that play roles in bone morphogenesis contribute to trauma-induced HO， hence are well-validated pharmacological targets. That said， development of inhibitors， typically competitors of ATP binding， is inherently difficult due to the conserved nature of the active site of the 500+ human protein kinases. Since these enzymes are regulated via inherent plasticity， pharmacological chaperone-like drugs binding to another (allosteric) site could hypothetically modulate kinase conformation and activity. To test for such a mechanism， a surface pocket of ALK2 kinase formed largely by a key allosteric substructure was targeted by supercomputer docking of drug-like compounds from a virtual library. Subsequently， the effects of docked hits were further screened in vitro with purified recombinant kinase protein. A family of compounds with terminal hydrogen-bonding acceptor groups was identified that significantly destabilized the protein， inhibiting activity. Destabilization was pH-dependent， putatively mediated by ionization of a histidine within the allosteric substructure with decreasing pH. In vivo， nonnative proteins are degraded by proteolysis in the proteasome complex， or cellular trashcan， allowing for the emergence of therapeutics that inhibit through degradation of over-active proteins implicated in the pathology of diseases and disorders. Because HO is triggered by soft-tissue trauma and ensuing hypoxia， dependency of ALK destabilization on hypoxic pH imparts selective efficacy on the allosteric inhibitors， providing potential for safe prophylactic use.