Abstract
Structure–activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.
Highlights
activin receptorlike kinase-2 (ALK2) is a serine/threonine kinase in the bone morphogenetic protein (BMP) pathway and one of seven (ALK1−7) type-I receptors in the BMP and transforming growth factor beta (TGFβ) signaling pathways.1Signaling through ALK2 is deregulated in two disease contexts
We identified 6-pyrazole quinazolinone, 1, as a ligand efficient inhibitor of ALK2 (IC50 = 8.2 μM; LE = 0.45) through crossscreening of a focused kinase fragment library, using Invitrogen’s LanthaScreen binding assay. 1 shares features with reported ALK5 inhibitors such as PF-0367114813 and compound 19.14 These are known to bind to the hinge of ALK5 through a single polar contact at the N-1 position of the quinazolinone moiety, with the 2-methylpyridine directing toward the ALK5 Ser280 gatekeeper residue, forming a key water mediated hydrogen bond to Lys232 (Figure 2)
PF-03671148 has been shown to be selective against ALK1 likely due a larger gate keeper (Thr) causing a clash with the pyridine substituent
Summary
ALK2 (gene: ACVR1) is a serine/threonine kinase in the bone morphogenetic protein (BMP) pathway and one of seven (ALK1−7) type-I receptors in the BMP and transforming growth factor beta (TGFβ) signaling pathways.. Journal of Medicinal Chemistry protein kinase inhibitor, but was found in a zebrafish embryo dorsalization assay to selectively inhibit BMP signaling through SMAD1/5/8.6 Further development led to LDN-193189,7 LDN-212854,8 and ML347,9 which had improved microsomal stability, potency, and selectivity. These molecules demonstrated efficacy in mouse models of FOP.. A second series of inhibitor based on a pyridine core (e.g., K0228811 and LDN-21411712), with equivalent biochemical potency and improved kinome selectivity, has been reported (Figure 1) These molecules demonstrated efficacy in mouse models of FOP. these compounds have a number of kinase off-targets and display dose-limiting toxicity with a 10% loss in body weight in animal models. A second series of inhibitor based on a pyridine core (e.g., K0228811 and LDN-21411712), with equivalent biochemical potency and improved kinome selectivity, has been reported (Figure 1)
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