Development of Next-Generation Poly(ADP-Ribose) Polymerase 1–Selective Inhibitors

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use of PARP inhibitors for certain rational combination strategies, such as chemotherapy and targeted therapy regimens. Currently approved PARP inhibitors are essentially equipotent against PARP1 and PARP2 enzymes. In this review, we describe the development of next-generation PARP1-selective inhibitors that have entered phase I clinical trials. These inhibitors have demonstrated increased PARP1 inhibitory potency and exquisitely high PARP1 selectivity in preclinical studies—features that may lead to improved clinical efficacy and a wider therapeutic window. First-in-human clinical trials seeking to establish the safety, tolerability, and recommended phase II dose, as well as antitumor activity of these novel agents, have commenced. If successful, this next-generation of PARP1-selective agents promises to build on the succeses of current PARP inhibitor treatment paradigms in cancer medicine.

Does PARP Inhibition Sensitize Chondrosarcoma Cell Lines to Chemotherapy or Radiotherapy? Results From a Three-dimensional Spheroid Cell Model

“…Toxicity could be overcome through better formulation strategies, such as a nanoparticle formulation of talazoparib, which was effective in reducing toxicity in xenografts with Ewing sarcoma [ 5 ]. In the future, discovery of next-generation selective PARP inhibitors, such as AZD5305, which is currently in clinical development, will further improve the pharmacologic profile and reduce adverse effects [ 29 ]. These options could be considered in the design of future animal model studies.…”

Bibliometric analysis of research trends on the combination of immune checkpoint inhibitors and PARP inhibitors in solid tumors

“…First, improvement of the efficacy and safety of the combined therapy requires further evaluation in the future clinical studies, aiming to enhance the efficiency and decrease the chances of toxic adverse effects. For example, the development of selective PARPi in preclinical studies have demonstrated higher potency which may provide better clinical efficacy and broader spectrum of treatment [ 105 , 106 ]. Second, it is critical to screen and target the patient groups that benefit the most from the combination therapy.…”

A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers

“…Although clinical benefits of PARP inhibitors have been proved, safety issues such as hematological toxicity need to be addressed ( Farres et al, 2013 ; LaFargue et al, 2019 ). The next generation of PARP inhibitors is under development, targeting selective PARP1, to remedy the adverse events caused by inhibition of PARP2 ( Curtin and Szabo, 2020 ; Dias et al, 2021 ; Johannes et al, 2021 ; Ngoi et al, 2021 ). Secondly, the PK characteristics of YHP-836 did not support its further development.…”