SIAIS178

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].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Bcr-Abl

Signaling Pathways >> PROTAC >> PROTAC

VHL

Bcr-Abl:24 nM (IC50)

SIAIS178 (1-100 nM; for 16 hours) significantly reduces the BCR-ABL protein levels in a concentration dependent manner. SIAIS178 significantly inhibits the phosphorylation of BCR-ABL and the substrates STAT5[1]. SIAIS178 (1, 10, 100, 1000 nM) exerts significant antiproliferative activity in BCR-ABL driven CML cell lines. SIAIS178 retains potency and selectivity against the BCR-ABL driven cell lines[1]. Western Blot Analysis[1] Cell Line: K562 cells Concentration: 1, 3, 10, 30, 100 nM Incubation Time: 16 hours Result: Significantly reduced the BCR-ABL protein levels in a concentration dependent manner.

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.

[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.