SIAIS178 is a Potent and Selective PROTAC-Based BCR-ABL Degrader
Posted On 2020-11-19
Proteolysis targeting chimeras (PROTACs) work by inducing selective intracellular proteolysis rather than acting as a conventional enzyme inhibitor. Besides, PROTACs consists of two covalently linked protein-binding molecules. One can engage an E3 ubiquitin ligase, and another binds to a target protein meant for degradation. Moreover, PROTACs need only to bind their targets with high selectivity rather than inhibit the target protein’s enzymatic activity. The chimeric molecules recruit the target protein and E3 ubiquitin ligase near the space, induce the target protein to ubiquitinate, and then degraded by the proteasome. Furthermore, oncogenic fusion protein BCR-ABL is the driving force of leukemia in chronic myeloid leukemia (CML). Furthermore, BCR-ABL has constitutively activated ABL tyrosine kinase activity, which can stimulate downstream signaling pathways and lead to uncontrolled proliferation of CML. SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology.
SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology.
But, how does SIAIS178 protect against cancer cells via BCR-ABL? Let’s discuss it in detail. First of all, SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology with an IC50 of 24 nM. Nonetheless, SIAIS178 causes effective degradation of BCR-ABL protein by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Additionally, SIAIS178 has anticancer activity.
In the second place, SIAIS178 with 1-100 nM for 16 hours significantly reduces the BCR-ABL protein levels in a concentration-dependent manner. Additionally, SIAIS178 significantly inhibits the phosphorylation of BCR-ABL and the substrates STAT5. Particularly, SIAIS178 exerts significant antiproliferative activity in BCR-ABL driven CML cell lines. SIAIS178 retains potency and selectivity against the BCR-ABL has driven cell lines.
Last but not the least, SIAIS178 with 5-45 mg/kg for12 days by IP attenuates tumor progression in a dose-dependent manner. Particularly, SIAIS178 has T1/2 of 3.82 and 12.35 hours and Cmax of 1165.2 nM and 30 nM for iv and IP, respectively.
All in all, SIAIS178 is a potent and selective BCR-ABL degrader based on PROTAC technology.
Zhao Q, et al. J Med Chem. 2019 Oct 24;62(20):9281-9298.