Passeri Daniela, Camaioni Emidio, Liscio Paride, Sabbatini Paola, Ferri Martina, Carotti Andrea, Giacchè Nicola, Pellicciari Roberto, Gioiello Antimo, Macchiarulo Antonio
TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
ChemMedChem. 2016 Jun 20;11(12):1219-26. doi: 10.1002/cmdc.201500391. Epub 2015 Oct 1.
Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.
近年来，聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂作为具有多方面功能的抗癌药重新引起了人们的关注。尤其令人兴奋的进展包括奥拉帕尼（Lynparza）获批用于治疗携带BRCA1/2突变的难治性卵巢癌，以及对PARP-1抑制剂多药理学的认识不断加深。这篇综述文章的目的是为读者全面概述PARP-1抑制剂多药理学的不同层面，包括1）家族间多药理学、2）家族内多药理学和3）多信号多药理学。文中讨论了在深入了解PARP-1抑制剂这些多靶点非依赖性和靶点依赖性活性的分子基础方面取得的进展，并展望了更好地理解多药理学在解释为什么一些候选药物在临床环境中比其他药物效果更好方面可能产生的潜在影响，尽管这些药物作用于相同靶点且抑制效力相似。
