Ullrich, Thomas, Kramer, Ina, Guth-Gundel, Sabine, Teixeira-Fouchard, Sylvie, Dekker, Carien, Hinniger, Alexandra, Head, Victoria, Nikolaus, Stiefl, Luca, Arista, Sven, Weiler and Kneissel, Michaela (2025) Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase‑2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva. ACS medicinal chemistry letters, 16 (11). pp. 2328-2335. ISSN 1948-5875

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease leading to progressive soft tissue heterotopic ossification (HO) with no curative treatment available to date. It is caused by gain-of-function mutations in the activin A type-1 receptor ACVR1/ALK2, a member of the bone morphogenetic protein (BMP) type I receptor family. Most recent clinical trials in FOP have adopted for the first time on-target therapies to normalize the aberrant ALK2 receptor activity. Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species. Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials.

Item Type:	Article
Date Deposited:	12 Dec 2025 00:45
Last Modified:	12 Dec 2025 00:45
URI:	https://oak.novartis.com/id/eprint/59125