luspatercept   Click here for help

GtoPdb Ligand ID: 10538

Synonyms: ACE-536 | ACE536 | luspatercept-aamt | Reblozyl®
Approved drug
luspatercept is an approved drug (FDA (2019), EMA (2020))
Compound class: Peptide or derivative
Comment: Luspatercept (ACE-536) is a fusion protein comprising human ACVR2B (activin receptor type 2B) extracellular domain (which is mutated to reduce activin binding), fused with human immunoglobulin G1 Fc fragment [2]. Mechanistically luspatercept acts as a ligand trap for growth/differentiation factor-11 (GDF11; and other Smad2/3-activating ligands), which reduces GDF11-induced Smad2/3 activation, and blocks the inhibitory effect of GDF11 on erythroid precursor maturation. Functionally, it promotes maturation of late-stage erythroid precursors, which is in contrast to erythropoietin, which stimulates proliferation of early-stage erythrocyte precursors. Using Gdf11 knockout, Guerra et al. (2019) dispute GDF11 as the molecular target of luspatercept and its proposed inhibitory effect on late erythropoiesis [1]. They do not propose an alternative mechanism of action.
Bioactivity Comments
In contrast to the broad binding profile detected in cell free SPR analysis, in cell-based reporter gene assays ACE-536 only inhibited GDF11- and GDF8-induced Smad2/3 signalling. It did not inhibit signalling induced by other ligands including activins and TGF-β1 [2].
Selectivity at ligand targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
growth/differentiation factor-11 Hs Fusion protein Binding 10.1 pKd - 2
⤷ pKd 10.1 (Kd 7.4x10-11 M) [2]
Description: Binding to GDF11 determined by surface plasmon resonance (SPR).
BMP-10 Hs Fusion protein Binding 10.1 pKd - 2
⤷ pKd 10.1 (Kd 8.7x10-11 M) [2]
Description: Binding to BMP10 determined by surface plasmon resonance (SPR).
BMP-6 Hs Fusion protein Binding 10.1 pKd - 2
⤷ pKd 10.1 (Kd 9x10-11 M) [2]
Description: Binding to BMP6 determined by surface plasmon resonance (SPR).
myostatin Hs Fusion protein Binding 9.7 pKd - 2
⤷ pKd 9.7 (Kd 2x10-10 M) [2]
Description: Binding to GDF8 determined by surface plasmon resonance (SPR).
activin B Hs Fusion protein Binding 9.2 pKd - 2
⤷ pKd 9.2 (Kd 6.2x10-10 M) [2]
Description: Binding to activin B determined by surface plasmon resonance (SPR).
BMP-9 Hs Fusion protein Binding 8.6 pKd - 2
⤷ pKd 8.6 (Kd 2.7x10-9 M) [2]
Description: Binding to BMP9 determined by surface plasmon resonance (SPR).
activin A Hs Fusion protein Binding 7.6 pKd - 2
⤷ pKd 7.6 (Kd 2.3x10-8 M) [2]
Description: Binding to activin B determined by surface plasmon resonance (SPR).