Discovery and development of TRND482477/KER-047 for treating ALK2 dysfunction disorders: FOP and anemia resulting from Iron imbalance

Authors

• K Shamim
• X Hu
• W Zheng
• P Sanderson
• A Wang
• X Xu
• W Huang
• J Lachey
• J Seehra

Abstract

Abstract: Activin receptor like kinases (ALK 1-7) are involved in bone morphogenetic protein (BMP) and transforming growth factor-B (TGF-B) signaling. They play important roles in various biological processes; controlling the development and regulation of bone, heart, nervous and reproductive systems, and hepcidin regulated iron homeostasis. Applications of an ALK2 selective inhibitor include the treatment of heterotopic ossification and anemias. A gain of function germline mutation in ACVR1, the gene encoding ALK2, has been identified in the ultrarare congenital malformation syndrome, fibrodysplasia ossificans progressive (FOP) which is characterized by the ossification of soft tissues. Herein, we describe the discovery and development of a selective bioavailable ALK2 inhibitor TRND477, effective in models of FOP. TRND477 (KER047) is currently in Phase 2 clinical trials for iron-refractory iron deficiency anemia (IRIDA).

Scientific Focus Area: Chemical Biology

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