Centko Ryan M, Carlile Graeme W, Barne Isabel, Patrick Brian O, Blagojevic Polina, Thomas David Y, Andersen Raymond J
Department of Chemistry and Department of Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z1.
Departments of Biochemistry and Human Genetics and The Cystic Fibrosis Translational Research Centre, McGill University, Montréal, Québec, Canada H3G 1Y6.
ACS Omega. 2020 Sep 29;5(40):25593-25604. doi: 10.1021/acsomega.0c02467. eCollection 2020 Oct 13.
The marine natural product latonduine A () shows F508del-cystic fibrosis transmembrane regulator (CFTR) corrector activity in cell-based assays. Pull-down experiments, enzyme inhibition assays, and siRNA knockdown experiments suggest that the F508del-CFTR corrector activities of latonduine A and a synthetic analogue MCG315 () result from simultaneous inhibition of PARP3 and PARP16. A library of synthetic latonduine A analogs has been prepared in an attempt to separate the PARP3 and PARP16 inhibitory properties of latonduine A with the goal of discovering selective small-molecule PARP3 and PARP16 inhibitory cell biology tools that could confirm the proposed dual-target F508del-CFTR corrector mechanism of action. The structure activity relationship (SAR) study reported herein has resulted in the discovery of the modestly potent (IC 3.1 μM) PARP3 selective inhibitor (±)-5-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1-benzo[]azepin-1-one () that shows 96-fold greater potency for inhibition of PARP3 compared with its inhibition of PARP16 and the potent (IC 0.362 μM) PARP16 selective inhibitor (±)-7,8-dichloro-5-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydro-1-benzo[]azepin-1-one () that shows 205-fold selectivity for PARP16 compared with PARP3 . At 1 or 10 μM, neither or alone showed F508del-CFTR corrector activity, but when added together at 1 or 10 μM each, the combination exhibited F508del-CFTR corrector activity identical to 1 or 10 μM latonduine A (), respectively, supporting its novel dual PARP target mechanism of action. Latonduine A () showed additive corrector activity in combination with the clinically approved corrector VX809, making it a potential new partner for cystic fibrosis combination drug therapies.
海洋天然产物拉通杜因A（）在基于细胞的实验中显示出F508del-囊性纤维化跨膜传导调节因子（CFTR）校正活性。下拉实验、酶抑制实验和siRNA敲低实验表明，拉通杜因A和一种合成类似物MCG315（）的F508del-CFTR校正活性源于对PARP3和PARP16的同时抑制。已制备了一个合成拉通杜因A类似物文库，试图分离拉通杜因A的PARP3和PARP16抑制特性，目标是发现选择性小分子PARP3和PARP16抑制性细胞生物学工具，以证实所提出的双靶点F508del-CFTR校正作用机制。本文报道的构效关系（SAR）研究发现了中等效力（IC 3.1 μM）的PARP3选择性抑制剂（±）-5-羟基-4-苯基-2,3,4,5-四氢-1-苯并[]氮杂卓-1-酮（），其对PARP3的抑制效力比对PARP16的抑制效力高96倍，以及强效（IC 0.362 μM）的PARP16选择性抑制剂（±）-7,8-二氯-5-羟基-4-（吡啶-2-基）-2,3,4,5-四氢-1-苯并[]氮杂卓-1-酮（），其对PARP16的选择性比对PARP3高205倍。在1或10 μM时，单独的或均未显示出F508del-CFTR校正活性，但当以1或10 μM的浓度一起添加时，该组合分别表现出与1或10 μM拉通杜因A（）相同的F508del-CFTR校正活性，支持其新的双PARP靶点作用机制。拉通杜因A（）与临床批准的校正剂VX809联合使用时显示出相加的校正活性，使其成为囊性纤维化联合药物治疗的潜在新伙伴。
