An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva

被引：12

作者：

Davis, Alison J. ^{[1
,4
]}

Brooijmans, Natasja ^{[1
,5
]}

Brubaker, Jason D. ^{[1
]}

Stevison, Faith ^{[1
,6
]}

LaBranche, Timothy P. ^{[1
]}

Albayya, Faris ^{[1
]}

Fleming, Paul ^{[1
,7
]}

Hodous, Brian L. ^{[1
,8
]}

Kim, Joseph L. ^{[1
]}

Kim, Sean ^{[1
,9
]}

Lobbardi, Riadh ^{[1
,10
]}

Palmer, Michael ^{[1
,11
]}

Sheets, Michael P. ^{[1
]}

Vassiliadis, John ^{[1
,12
]}

Wang, Ruduan ^{[1
]}

Williams, Brett D. ^{[1
,13
]}

Wilson, Douglas ^{[1
]}

Xu, Lan ^{[1
,14
]}

Zhu, Xing Julia ^{[1
,15
]}

Bouchard, Keith ^{[2
]}

Hunter, Jeffrey W. ^{[2
]}

Graul, Chris ^{[3
,16
]}

Greenblatt, Elliot ^{[3
]}

Hussein, Amira ^{[3
]}

Lyon, Morgan ^{[3
]}

Russo, Joelle ^{[3
,17
]}

Stewart, Rachel ^{[3
]}

Dorsch, Marion ^{[1
,18
]}

Guzi, Timothy J. ^{[1
,19
]}

Kadambi, Vivek ^{[1
,9
]}

Lengauer, Christoph ^{[1
,20
]}

Garner, Andrew P. ^{[1
,20
]}

机构：

[1] Blueprint Med Corp, Cambridge, MA 02139 USA

[2] Alexion Pharmaceut, Boston, MA 02210 USA

[3] Invicro, Boston, MA 02210 USA

[4] Dunad Therapeut, Cambridge, MA 02142 USA

[5] Scorp Therapeut, Boston, MA 02110 USA

[6] constellat Pharmaceut, Boston, MA 02210 USA

[7] akebia Therapeut, Cambridge, MA 02142 USA

[8] recludix Pharm, Cambridge, MA 02141 USA

[9] IDRx, Plymouth, MA 02360 USA

[10] C4 Therapeut, Watertown, MA 02472 USA

[11] Bicycle Therapeut, Cambridge, MA 02140 USA

[12] relay Therapeut, Cambridge, MA 02142 USA

[13] insitro, South San Francisco, CA 94080 USA

[14] ikena oncol, Cambridge, MA 02210 USA

[15] nested Therapeut, Cambridge, MA 02139 USA

[16] TRIA Architects Inc, Boston, MA 02210 USA

[17] Bristol Myers Squibb, Cambridge, MA 02141 USA

[18] atavistik Bio, Cambridge, MA 02139 USA

[19] MOMA Therapeut, Cambridge, MA 02140 USA

[20] curie Bio, Cambridge, MA 02115 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2024年 / 16卷 / 749期

关键词：

FOP;

D O I：

10.1126/scitranslmed.abp8334

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2(R206H). In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2(R206H) inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2(R206H) binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2(R206H) with high affinity, inhibiting signaling from ALK2(R206H) and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2(R206H) mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2(R206H) mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2(R206H) mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

引用

页数：15

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