Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Jingcao Zheng; Zhengyu Li; Wenjiao Min

doi:10.3389/fphar.2022.979873

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Front Pharmacol. 2023 Jan 23:13:979873. doi: 10.3389/fphar.2022.979873. eCollection 2022.

Authors

Jingcao Zheng^{1

2}, Zhengyu Li^{1

2}, Wenjiao Min³

Affiliations

¹ Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.
² Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China.
³ Psychosomatic Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.

Abstract

The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 members, which have been demonstrated as having effects on a series of cellular processes, including DNA replication and repair. PARP inhibitors (PARPi) suppress DNA repair through "PARP trapping", thus, constitute an important treatment option for cancer nowadays. In addition, PARP inhibition and homologous recombination repair (HRR) defects are synthetically lethal, giving a promising therapeutic for homologous recombination repair deficient (HRD) tumors including BRCA mutation. However, overlapping hematologic toxicity causes PARPi to fail in combination with some first-line chemotherapies. Furthermore, recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for antitumor activity in HRD cancer models. Currently approved PARPi have shown varying levels of selectivity for the entire 17-member PARP family, hence contribute to toxicity. Together, these findings above have provided the necessity and feasibility of developing next-generation PARPi with improved selectivity for PARP1, expanding significant clinical values and wide application prospects both in monotherapy and combination with other anticancer agents. In this review, we summery the latest research of current approved PARPi, discuss the current status and future promise of next-generation PARP1-selective inhibitor AZD5305, including its reported progress up to now and anticipated impact on clinical.

Keywords: AZD5305; PARP inhibitors; improved selectivity; novel therapy; oncology.

Publication types

Review

Grants and funding

The Department of Science and Technology of Sichuan Province (grant number 21PJ050).