Felicetti Tommaso, Di Iacovo Nicola, Della Fazia Maria Agnese, Piobbico Danilo, Pieroni Stefania, Pacetti Martina, Yu Jialing, Sun Yilun, Massari Serena, Barreca Maria Letizia, Sabatini Stefano, Tabarrini Oriana, Cecchetti Violetta, Wang Fei, Pommier Yves, Morlando Mariangela, Servillo Giuseppe, Manfroni Giuseppe
Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy
Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy
RSC Med Chem. 2024 Sep 27;16(1):98-124. doi: 10.1039/d4md00649f.
MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI values 13.52-31.04 μM) and CC = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR ( = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.
微小RNA（miRNA）在卵巢癌（OC）发病机制中起关键作用，且miRNA加工过程可成为药物干预的对象。通过利用我们内部的喹诺酮文库，我们将基于细胞的筛选与药物化学研究相结合，最终得到了衍生物33，其对不同细胞系具有抗OC活性（GI值为13.52 - 31.04 μM），且CC = 142.9 μM。化合物33对其他癌细胞也保留抗癌活性，并与顺铂对顺铂耐药的A2780细胞表现出协同作用。化合物33通过表面等离子体共振（SPR）（KD = 4.09 μM）和热位移分析与TRBP结合，其活性依赖于TRBP，导致小干扰RNA（siRNA）和miRNA成熟受到调节。与唯一被鉴定为miRNA成熟调节剂的喹诺酮类药物依诺沙星相比，衍生物33对OC细胞表现出更强的效力以及对TRBP更强的结合亲和力。因此，33代表了开发具有独特作用机制的新型抗OC药物的一个有前景的模板。
