Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function  Felix Y. Feng, Johann S. de Bono, Mark A. Rubin, Karen E. Knudsen  Molecular Cell  Volume 58, Issue 6, Pages 925-934 (June 2015) DOI: 10.1016/j.molcel.2015.04.016 Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 1 Schematic Highlighting the Translational Implications of the Dual Roles of PARP1 in DNA Repair and Transcriptional Regulation Multiple preclinical studies have demonstrated the dual roles of PARP-1 in facilitating DNA repair and in regulating transcription. The findings from these studies have resulted in the initiation of greater than 100 clinical trials. PARP-1 inhibitors have been utilized, as monotherapy or in combination with cytotoxic agents, to target DNA repair in the context of clinical trials aimed at improving cancer therapy. PARP-1 inhibitors have also been investigated as a strategy for suppressing transcriptional drivers of disease in the setting of both cancer and non-cancer conditions, such as stroke and myocardial infarction. Representative clinical trials are highlighted for each of these translational settings. Molecular Cell 2015 58, 925-934DOI: (10.1016/j.molcel.2015.04.016) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 2 Distribution of PARP Inhibitor Trials by Various Characteristics PARP inhibitor studies were identified on the clinical trial repository website (https://www.clinicaltrials.gov/) using the keyword “PARP.” This search, completed in early March of 2015, identified 149 trials. Of these studies, 33 were excluded because they had been withdrawn prior to enrollment or because they did not utilize a true PARP inhibitor. Specifically, it should be noted that all studies including iniparib (BSI-201) were excluded, as it has been determined that this agent actually has poor selectivity toward PARP function and does not meet the current criteria for a bona fide PARP1 inhibitor (Patel et al., 2012). Of the remaining 116 studies, the distribution of trials is shown by indication (cancer versus non-cancer indication) in Figure 2A and by phase (0–3) in Figure 2B. Of the 112 studies using PARP1 as cancer therapy, the distribution of these trials is then shown by disease site (Figure 2C), therapy (mono- versus combination therapy, Figure 2D), and biomarker selection (Figure 2E). Molecular Cell 2015 58, 925-934DOI: (10.1016/j.molcel.2015.04.016) Copyright © 2015 Elsevier Inc. Terms and Conditions