Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Cell. 2024 May 9;187(10):2536-2556.e30. doi: 10.1016/j.cell.2024.03.027. Epub 2024 Apr 22.
Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer 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 covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.
半胱氨酸靶向化学蛋白质组学平台加速了针对癌症中广泛靶点的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，我们开发了“DrugMap”，这是一个跨 416 种癌细胞系编译的半胱氨酸配体可及性图谱。我们出人意料地发现，半胱氨酸配体可及性在癌细胞系之间存在差异，我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，我们确定了 NF-κB1 和 SOX10 中的可作用半胱氨酸，并开发了相应的共价配体来阻断这些转录因子的活性。我们证明 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。我们的研究结果揭示了癌症中半胱氨酸配体可及性的异质性，指出了驱动半胱氨酸靶向的细胞内在特征，并说明了使用共价探针来破坏致癌转录因子活性的方法。
