AstraZeneca Submits Clinical Application in China for Next-Generation PARP1-Selective Inhibitor AZD5305
Jul 06, 2021 20:47
CST Updated
20:47
AstraZeneca
Biopharmaceutical Manufacturer
On July 6, the CDE official website showed,AstraZenecaThe clinical trial application for the second-generation PARP (highly selective PARP1) inhibitor AZD5305 has been accepted by the National Medical Products Administration (NMPA).
Since olaparib was approved in 2014 for BRCA-mutated (BRCAm) ovarian cancer, multiple PARP inhibitors have been developed and have achieved widespread success. However, the drug'sAdverse Reactionslimits their ability to be used in combination with chemotherapeutic agents.
Most first-generation PARP inhibitors were developed and optimized prior to the discovery of the PARP1-DNA trapping concept, which is the mechanism by which PARP inhibitors exert synthetic lethality in BRCAm cells. Furthermore, because first-generation PARP inhibitors were not optimized for selectivity within the PARP family, this may lead to adverse side effects, including gastrointestinal toxicity induced by tankyrase inhibition or hematologic toxicity resulting from PARP2 inhibition.
Therefore, researchers began searching for a best-in-class second-generation PARP inhibitor that demonstrates high selectivity for PARP1 over the other 16 members of the PARP family, while also acting as a highly efficient PARP1-DNA trapping agent.
The amino acid sequences of PARP1 and PARP2 are highly similar, with most residues surrounding the nicotinamide-binding site being identical. However, key residue differences exist within the helical domain that modulates the nicotinamide-binding pocket. Based on this, AstraZeneca identified the lead compound AZ4554 and, through structural optimization, developed the clinical candidate AZD5305.