Identification of 6‑Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer

Increasing
evidence has demonstrated that oxidative phosphorylation
(OXPHOS) is closely associated with the progression of pancreatic
cancer (PC). Given its central role in mitochondrial transcription,
the human mitochondrial RNA polymerase (POLRMT) is a promising target
for developing PC treatments. Herein, structure–activity relationship
exploration led to the identification of compound S7,
which was the first reported POLRMT inhibitor possessing single-digit
nanomolar potency of inhibiting PC cells proliferation. Mechanistic
studies showed that compound S7 exerted antiproliferative
effects without affecting the cell cycle, apoptosis, mitochondrial
membrane potential (MMP), or intracellular reactive oxygen species
(ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model
with a tumor growth inhibition (TGI) rate of 64.52% demonstrating
significant improvement compared to the positive control (44.80%).
In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate
for PC treatment.

越来越多的证据表明，氧化磷酸化（OXPHOS）与胰腺癌（PC）的进展密切相关。鉴于人类线粒体RNA聚合酶（POLRMT）在线粒体转录中发挥核心作用，其是开发胰腺癌治疗手段的极具潜力的靶点。本研究通过构效关系（structure–activity relationship）探索，成功鉴定得到化合物S7——这是首个被报道的、具有单纳摩尔级抑制胰腺癌细胞增殖活性的POLRMT抑制剂。机制研究表明，化合物S7可在MIA PaCa-2细胞中发挥抗增殖活性，且未对该细胞的细胞周期、细胞凋亡、线粒体膜电位（MMP）以及细胞内活性氧（ROS）水平造成影响。值得注意的是，化合物S7可在MIA PaCa-2异种移植瘤模型中有效抑制肿瘤生长，肿瘤生长抑制率（TGI）达64.52%，相较于阳性对照组的44.80%具有显著提升。综上，本研究丰富了POLRMT抑制剂的构效关系研究体系，化合物S7作为胰腺癌治疗候选药物，其成药性值得开展进一步深入研究。