PO.ET02.07 · 实验与分子治疗
从不可成药到可干预：致癌转录因子小分子调节剂的转录组学发现
From undruggable to actionable: Transcriptomic discovery of small-molecule modulators of oncogenic transcription factors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
转录因子(TF)及其相关信号网络仍是肿瘤药物发现中最具挑战性且探索最不充分的靶点之一。为弥补这一空白，QUANTRO Therapeutics开发了一个转录组学发现平台，通过检测细胞受扰动后早至一小时内新生RNA合成的变化来测量细胞转录活性。与仅以有限的时间分辨率捕获稳态mRNA丰度的传统RNA-seq方法不同，该平台直接定量即时转录反应，提供TF活性的高保真读出。QUANTRO平台目前包含三种互补的检测方法——QUANTROsens、QUANTROseq和QUANTROslam——它们共同实现对转录调节剂的识别、确认和机制表征。特别是，QUANTROseq能够高通量生成由小分子诱导的动态转录"指纹"，可直接与特定靶蛋白经急性、受控降解所产生的特征进行比较。通过关联这些谱图，该平台可精确区分直接作用于TF或辅因子的化合物与那些通过上游通路发挥间接效应的化合物。作为其能力的示范，我们展示了对已发表MYC抑制剂的系统性重新评估，揭示了传统转录组学或报告基因检测如何会将间接调节剂误分类为直接MYC抑制剂。利用这项技术，QUANTRO已启动针对c-MYC和YAP/TEAD等关键致癌驱动因素的筛选活动，从而识别出多个具有明确靶点活性和极小脱靶效应的高质量命中簇。总体而言，这些研究证明了动态转录组分析在扩展可成药靶点空间、加速首创疗法发现以及阐明癌症进展背后转录调控机制方面的力量。
查看英文原文 English abstract
Transcription factors (TFs) and their associated signaling networks remain among the most challenging and underexplored targets in oncology drug discovery. To address this gap, QUANTRO Therapeutics has developed a Transcriptomic Discovery Platform that measures cellular transcriptional activity by detecting changes in nascent RNA synthesis as early as one hour after cellular perturbation. Unlike conventional RNA-seq approaches, which capture only steady-state mRNA abundance with limited temporal resolution, this platform directly quantifies immediate transcriptional responses, providing a high-fidelity readout of TF activity.The QUANTRO platform currently comprises three complementary assays-QUANTROsens, QUANTROseq, and QUANTROslam-that together enable the identification, confirmation, and mechanistic characterization of transcriptional modulators. In particular, QUANTROseq enables high-throughput generation of dynamic transcriptional “fingerprints” induced by small molecules, which can be directly compared with signatures resulting from acute, controlled degradation of specific target proteins. By correlating these profiles, the platform precisely distinguishes compounds acting directly on TFs or cofactors from those exerting indirect effects through upstream pathways. As a demonstration of its capabilities, we present a systematic re-evaluation of published MYC inhibitors, revealing how traditional transcriptomic or reporter-based assays can misclassify indirect modulators as direct MYC inhibitors.Leveraging this technology, QUANTRO has initiated screening campaigns targeting key oncogenic drivers such as c-MYC and YAP/TEAD, leading to the identification of multiple high-quality hit clusters with clear on-target activity and minimal off-target effects. Collectively, these studies demonstrate the power of dynamic transcriptomic profiling to expand the druggable target space, accelerate discovery of first-in-class therapeutics, and illuminate transcriptional control mechanisms underlying cancer progression.
利益披露 Disclosure
A. Sabò, None.