AZD-5305 is a potent and highly selective PARP1 inhibitor. AZD5305 dosed at 0.1mg/kg QD or higher for 35 days delivered about 90% regression in the BRCA1m triple-negative breast cancer (TNBC) xenograft model MDA-MB-436.
Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair Julio Morales, Longshan Li,et al.| Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr. 2014;24(1):15-28.| https://pubmed.ncbi.nlm.nih.gov/24579667/. AZD5305 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. It is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro. AZD5305 combines excellent potency to PARP1 with superior selectivity toward PARP2, reaching almost 10,000-fold. AZD5305 exhibited very low plasma clearances (CLp) of 0.23, 1.1, 0.33, and 0.84 mL/min/kg and generally low steady-state volumes of distribution (Vss) of 0.17,0.38, 0.30, and 0.38 L/kg in the mouse, rat, dog, and monkey, respectively. The resulting plasma half-lives were 8.0, 4.6, 10,and 7.1 h, respectively. The oral bioavailability of AZD5305 was high across all species, consistent with the low hepatic clearance and a high fraction absorbed. The unbound clearance of ≤34 mL/min/kg, in combination with high potency, was expected to drive low efficacious doses in vivo which was predicted to carry through to humans based on the equally low in vitro CLint values[1].
搜索
