美国马萨诸塞州总医院癌症中心Liron Bar-Peled，Michael S. Lawrence和Mariko Takahashi共同合作，近期取得重要工作进展。他们研究提出了DrugMap，一种半胱氨酸配位性的定量泛癌分析方法。相关研究成果2024年4月22日在线发表于《细胞》杂志上。

据介绍，以半胱氨酸为主的化学蛋白质组学平台加速了用于癌症多种靶点共价抑制剂的临床开发。然而，不同的致癌环境如何影响半胱氨酸靶向仍然未知。

为了解决这个问题，研究人员开发了“DrugMap”，这是一个在416个癌症细胞系中汇编的半胱氨酸配位性图谱。研究人员发现，半胱氨酸连接性在癌症细胞系中不同，他们将其归因于细胞氧化还原状态、蛋白质构象变化和基因突变的差异。

利用这些发现，研究人员在NF-κB1和SOX10中鉴定了可操作的半胱氨酸，并开发了相应的共价配体来阻断这些转录因子的活性。研究证明NF-κB1探针阻断DNA结合，而SOX10配体增加SOX10-SOX10相互作用并破坏黑色素瘤转录信号传导。

总之，这一研究揭示了不同癌症中半胱氨酸配体性的异质性，指出了驱动半胱氨酸靶向的细胞内在特征，并说明了如何利用共价探针来破坏致癌转录因子的活性。

附：英文原文

Title: DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

Author: Mariko Takahashi, Harrison B. Chong, Siwen Zhang, Tzu-Yi Yang, Matthew J. Lazarov, Stefan Harry, Michelle Maynard, Brendan Hilbert, Ryan D. White, Heather E. Murrey, Chih-Chiang Tsou, Kira Vordermark, Jonathan Assaad, Magdy Gohar, Benedikt R. Dürr, Marianne Richter, Himani Patel, Gregory Kryukov, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Villanueva, Junbing Zhang, Maolin Ge, Farah Makram, Hanna Griesshaber, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, George Popoola, Inbal Rachmin, Neha Khandelwal, Jason R. Neil, Pei-Chieh Tien, Nicholas Chen, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lillian Bussema, Rui Dong, Lei Shi, Martin Q. Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, John Kastanos, Eugene Oh, David E. Fisher, Shyamala Maheswaran, Daniel A. Haber, Genevieve M. Boland, Moshe Sade-Feldman, Russell W. Jenkins, Aaron N. Hata, Nabeel M. Bardeesy, Mario L. Suvà

Issue&Volume: 2024-04-22

Abstract: Cysteine-focused chemical proteomic platforms have accelerated the clinical developmentof covalent inhibitors for a wide range of targets in cancer. However, how differentoncogenic contexts influence cysteine targeting remains unknown. To address this question,we have developed “DrugMap,” an atlas of cysteine ligandability compiled across 416cancer cell lines. We unexpectedly find that cysteine ligandability varies acrosscancer cell lines, and we attribute this to differences in cellular redox states,protein conformational changes, and genetic mutations. Leveraging these findings,we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalentligands that block the activity of these transcription factors. We demonstrate thatthe NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10interactions and disrupts melanoma transcriptional signaling. Our findings revealheterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic featuresdriving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenictranscription-factor activity.

DOI: 10.1016/j.cell.2024.03.027

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00318-0