ABS-752 hydrochloride is an orally active prodrug targeting CRBN-modulating molecular glue with selectivity in protein degradation. ABS-752 hydrochloride preferentially degrades GSPT1 and induces cytotoxicity through this degradation, while it also degrades NEK7, SALL4 and CK1α, with weaker degradation potency against CK1α. As a prodrug, ABS-752 hydrochloride requires metabolic activation to ABT-002 to form the active complex; VAP-1 mediates its conversion to an aldehyde intermediate. ABS-752 hydrochloride induces cell death, reduces cell viability, and exhibits antitumor activity, leading to regression and inhibition of tumor growth. ABS-752 hydrochloride shows no cytotoxicity in primary human hepatocytes. ABS-752 hydrochloride can be used in the research of hepatocellular carcinoma [1].
In Vivo, ABS-752 (1-10 mg/kg; p.o.; BID; 14 days) hydrochloride exhibits exceptional antitumor efficacy in the Hep3B xenograft model, with complete tumor regression observed at the 10 mg/kg BID dose[1]. ABS-752 (100 mg/kg; p.o.; BID; 20-21 days) hydrochloride induces tumor growth inhibition in 80% of tested HCC PDX models, with >50% TGI in four models and complete regression in one model at the 100 mg/kg BID dose[1]. ABS-752 (0.1 mg/kg; single dose) hydrochloride induces significant degradation of GSPT1 and NEK7 in non-human primates at a 0.1 mg/kg dose, with ~80% GSPT1 degradation observed 6 hours post-dose[1].
In Vitro, ABS-752 (72 h) hydrochloride exerts cytotoxic/cytostatic activity in 13 of 19 tested HCC cell lines, reducing viability by at least 50%[1]. ABS-752 (1-50 μM; 72 h) hydrochloride reduces viability in wild-type Hep3B cells, but has no effect on Hep3B GSPT1G575N cells, demonstrating that GSPT1 degradation drives its cytotoxic activity[1]. ABS-752 (0.1 nM-30 μM; 72 h) hydrochloride has viability-reducing activity in Hep3B cells that is dependent on VAP-1[1]. ABS-752 (6 h, 24 h) hydrochloride potently degrades GSPT1 (DC50 = 1 nM at 24 h), NEK7 (DC50 = 9 nM at 24 h), CK1α (DC50 = 35 nM at 24 h) in Hep3B cells, and SALL4 (DC50 = 40 nM at 24 h) in Kelly cells, with GSPT1 as the primary target showing near-complete degradation at early time points[1]. ABS-752 (0.1 μM; 6 h) hydrochloride preferentially degrades GSPT1, with greater degradation of NEK7 than CK1α[1]. ABS-752 (1-10 μM) hydrochloride does not form a biochemical ternary complex with CRBN and GSPT1, NEK7, CK1α, or IKZF1, but shows recruitment activity with SALL4[1]. ABS-752 (10 μM; 0-20 h) hydrochloride is converted to the aldehyde metabolite ABT-971 by recombinant mVAP-1[1]. ABS-752 (125-2500 μM; 15 min) hydrochloride is oxidized by recombinant human VAP-1 with a Km of 674 μM[1].
References:
[1]. Glaza P, et al. Targeted degradation of GSPT1 and NEK7 by a molecular glue prodrug for treatment of HCC. Communications chemistry. 2025 Aug 14;8(1):247.
In Vivo, ABS-752 (1-10 mg/kg; p.o.; BID; 14 days) hydrochloride exhibits exceptional antitumor efficacy in the Hep3B xenograft model, with complete tumor regression observed at the 10 mg/kg BID dose[1]. ABS-752 (100 mg/kg; p.o.; BID; 20-21 days) hydrochloride induces tumor growth inhibition in 80% of tested HCC PDX models, with >50% TGI in four models and complete regression in one model at the 100 mg/kg BID dose[1]. ABS-752 (0.1 mg/kg; single dose) hydrochloride induces significant degradation of GSPT1 and NEK7 in non-human primates at a 0.1 mg/kg dose, with ~80% GSPT1 degradation observed 6 hours post-dose[1].
In Vitro, ABS-752 (72 h) hydrochloride exerts cytotoxic/cytostatic activity in 13 of 19 tested HCC cell lines, reducing viability by at least 50%[1]. ABS-752 (1-50 μM; 72 h) hydrochloride reduces viability in wild-type Hep3B cells, but has no effect on Hep3B GSPT1G575N cells, demonstrating that GSPT1 degradation drives its cytotoxic activity[1]. ABS-752 (0.1 nM-30 μM; 72 h) hydrochloride has viability-reducing activity in Hep3B cells that is dependent on VAP-1[1]. ABS-752 (6 h, 24 h) hydrochloride potently degrades GSPT1 (DC50 = 1 nM at 24 h), NEK7 (DC50 = 9 nM at 24 h), CK1α (DC50 = 35 nM at 24 h) in Hep3B cells, and SALL4 (DC50 = 40 nM at 24 h) in Kelly cells, with GSPT1 as the primary target showing near-complete degradation at early time points[1]. ABS-752 (0.1 μM; 6 h) hydrochloride preferentially degrades GSPT1, with greater degradation of NEK7 than CK1α[1]. ABS-752 (1-10 μM) hydrochloride does not form a biochemical ternary complex with CRBN and GSPT1, NEK7, CK1α, or IKZF1, but shows recruitment activity with SALL4[1]. ABS-752 (10 μM; 0-20 h) hydrochloride is converted to the aldehyde metabolite ABT-971 by recombinant mVAP-1[1]. ABS-752 (125-2500 μM; 15 min) hydrochloride is oxidized by recombinant human VAP-1 with a Km of 674 μM[1].
References:
[1]. Glaza P, et al. Targeted degradation of GSPT1 and NEK7 by a molecular glue prodrug for treatment of HCC. Communications chemistry. 2025 Aug 14;8(1):247.