AMPTX-1 is a selective, orally active, covalent reversible BRD9 molecular glue degrader with a DC50 of 0.05 nM. AMPTX-1 selectively recruits BRD9 to the E3 ligase DCAF16. AMPTX-1 forms a ternary complex with BRD9 and a reversible covalent adduct with Cys58 on the surface of DCAF16. AMPTX-1 mediates BRD9 degradation via the proteasome and Cullin RING E3 ligase pathways. AMPTX-1 can be used in the research of solid tumors and hematological malignancies [1].
In Vivo, AMPTX-1-ent-1 (the highly active enantiomer of AMPTX-1) (50 mg/kg; p.o.; administered twice, sampled after a single dose) induces significant BRD9 degradation in tumor tissues in the MV4-11 xenograft mouse model[1].
In Vitro, AMPTX-1 (6 h) potently degrades endogenous BRD9 in MV4-11 cells (DC50 = 0.5 nM, Dmax = 93%) and MCF-7 cells (DC50 = 2 nM, Dmax = 70%) following 6 h treatment, with a hook effect at concentrations above 100 nM[1]. AMPTX-1 (6 h) -induced BRD9 degradation in BRD9-HiBiT HEK293 cells is dependent on proteasome function, Cullin RING E3 ligase activity, and BRD9 engagement, as pre-treatment with MLN4924, Bortezomib, or BI-7273 blocks degradation[1].
References:
[1]. Scott J. Hughes, et al. Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept. bioRxiv. January 02, 2025.
In Vivo, AMPTX-1-ent-1 (the highly active enantiomer of AMPTX-1) (50 mg/kg; p.o.; administered twice, sampled after a single dose) induces significant BRD9 degradation in tumor tissues in the MV4-11 xenograft mouse model[1].
In Vitro, AMPTX-1 (6 h) potently degrades endogenous BRD9 in MV4-11 cells (DC50 = 0.5 nM, Dmax = 93%) and MCF-7 cells (DC50 = 2 nM, Dmax = 70%) following 6 h treatment, with a hook effect at concentrations above 100 nM[1]. AMPTX-1 (6 h) -induced BRD9 degradation in BRD9-HiBiT HEK293 cells is dependent on proteasome function, Cullin RING E3 ligase activity, and BRD9 engagement, as pre-treatment with MLN4924, Bortezomib, or BI-7273 blocks degradation[1].
References:
[1]. Scott J. Hughes, et al. Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept. bioRxiv. January 02, 2025.