赖氨酸脱乙酰酶抑制剂 (KDACis) 是已批准用于治疗皮肤 T 细胞淋巴瘤 (CTCL)、外周 T 细胞淋巴瘤 (PTCL) 和多发性骨髓瘤的药物，但其细胞作用机制 (MoA) 和实质毒性的许多方面尚不清楚。为了更多地了解 KDACis 如何引发细胞反应，我们系统地测量了 21 种临床和临床前 KDACis 的乙酰化、磷酸化和蛋白质表达的剂量依赖性变化。例如，所得的 862,000 条剂量反应曲线揭示了组蛋白脱乙酰酶 (HDAC) 1、2、3 和 6 抑制剂的有限细胞特异性；乙酰化和磷酸化途径之间存在强烈的串扰；大多数药物反应性乙酰化位点定位于本质无序区域（IDR）；乙酰化在蛋白质结构中的作用未被充分认识； EP300 蛋白丰度在细胞质和细胞核之间发生变化。这个综合数据集可作为研究 KDACi 在细胞中作用的分子机制的资源，并且可以在 ProteomicsDB 中在线交互式探索。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.