| Hazard Information | Back Directory | [Description]
SIAIS178 is a potent BCR-ABL Degrader. SIAIS178 induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+ leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+ leukemia. | [Uses]
SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology with an IC50 of 24 nM. SIAIS178 causes effective degradation of BCR-ABL protein by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. SIAIS178 has anticancer activity[1]. | [in vivo]
SIAIS178 (ip; 5, 15, and 45 mg/kg; 12 days) attenuates tumor progression in a dose-dependent manner, as determined by serial volumetric measurement [1].
SIAIS178 (iv or ip; 2 mg/kg; 24 hours) has T1/2 of 3.82 and 12.35 hours and Cmax of 1165.2 nM and 30 nM for iv and ip, respectively[1].
| Animal Model: | NOD/SCID mice with termed K562-Luc[1] | | Dosage: | 5, 15, and 45 mg/kg | | Administration: | Ip; 12 days | | Result: | Attenuated tumor progression in a dose-dependent manner, as determined by serial volumetric measurement.
|
| Animal Model: | Female Wistar rats[1] | | Dosage: | 2 mg/kg (Pharmacokinetic Analysis) | | Administration: | Iv or ip; 24 hours | | Result: | Had T1/2 of 3.82 and 12.35 hours and Cmax of 1165.2 nM and 30 nM for iv and ip, respectively.
|
| [IC 50]
VHL; Bcr-Abl: 24 nM (IC50) | [References]
[1] Zhao Q, et al. Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. J Med Chem. 2019 Oct 24;62(20):9281-9298. DOI:10.1021/acs.jmedchem.9b01264 |
|
|