Activin A receptor, type I (ACVR1); A Target Enabling Package

Germline gain of function mutations in the gene <em>ACVR1</em> encoding the BMP receptor ALK2 lead to the rare congenital syndrome FOP in which aberrant signalling through the BMP signalling pathway leads to progressive heterotopic ossification in muscle and connective tissue. Identical somatic mutations have been identified in 25% of cases of the childhood brain tumour DIPG. Both conditions affect young children and have no approved therapies. Highly selective ALK2 kinase inhibitors are therefore desirable to achieve chronic treatment of children with safety. We prepared recombinant ALK2 kinase domain and solved structures of ALK2 in complex with new ATP-competitive inhibitors. We identified a novel allosteric pocket in the ALK2 kinase domain and took advantage of these structures to perform crystallographic fragment screening (XChem) using both a standard poised fragment library and a new mini-fragment library. This work identified a poised fragment for development as an allosteric ALK2 inhibitor, as well as mini-fragments exploiting new areas of the ATP and substrate binding pockets. <em>In vitro</em> and cellular assays are available to advance these compounds for drug development in collaboration with patient groups.