Novel ALK2 inhibitory compound may be a candidate FOP treatment

[Author: Laura Cowen]

Swiss researchers have identified a novel compound that selectively inhibits activin receptor-like kinase 2 (ALK2) and may be a future candidate for the treatment of fibrodysplasia ossificans progressive (FOP).

Writing in Bioorganic & Medicinal Chemistry Letters, Thomas Ullrich and colleagues from Novartis Pharma AG in Basel explain that ALK2 plays a key role in the pathogenesis of FOP as a result of a recurrent gain-of-function mutation (R206H) in the glycine-serine activation domain of the ALK2 type I bone morphogenic protein (BMP) receptor kinase.

The mutation results in the destabilization of the inactive conformation of ALK2, which leads to a series of cellular signaling events that ultimately bring about heterotopic endochondral ossification in affected patients.

Targeting ALK2 is therefore “a promising therapeutic treatment principle for FOP,” Ullrich et al remark.

They carried out a medium-throughput screening of their kinase inhibitor library and identified several compounds with biochemical potency and selectivity for ALK2. These included compound 2, which the researchers noted had “strikingly similar structural features” to a piperazine containing compound (compound 1) that had been discovered by a different research group and also had excellent cellular potency.

The researchers hypothesized that compounds 1 and 2 shared the same binding mode and believed that they could improve the pharmacokinetic properties of compound 2 by altering basic side chains and identifying cyclohexane replacements without affecting the binding of the 2-aminopyrazine-3-carboxamide scaffold.

Following a series of alterations, that often improved some features such as microsomal stability but then reduced others such as permeability, the researchers selected compound 23 for further characterization. This compound had high in vitro solubility, permeability, and microsomal stability.

Further analyses revealed that compound 23 was highly selective for ALK2R206H when compared with the transforming growth factor beta type I receptor protein kinase ALK5 and the BMP type 1 receptor protein kinase ALK6. There was lower selectivity over the BMP type I receptor protein kinases ALK1, ALK3, but the authors say that this “is consistent with previous reports highlighting the low differences in protein sequence homology between those BMP receptors.”

They also note that the “clinical safety of inhibiting ALK1, ALK3 and ALK6 is still under investigation” whereas inhibition of ALK5 has previously been associated with adverse cardiac events.

The investigators then used the DiscoveRx KINOMEscan® platform to measure the binding affinity of compound 23 for 468 different kinases. Overall, compound 23 interacted with just five kinases and had the strongest affinity for ALK2 and ALK6. However, ALK6 binding “did not translate in any corresponding ALK6 inhibitory activity,” they remark.

Ullrich and co-authors conclude: “High aqueous solubility, membrane permeability and microsomal stability make [compound] 23 an ideal candidate for pharmacokinetic profiling and determination of efficacy in rodent models of FOP.”

They add: “Further efforts will focus on establishing a structural model to rationalize the kinase selectivity profile of [compound] 23, and that work will be reported at a later stage.”

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