Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA.
Mol Cell. 2010 Jan 15;37(1):102-11. doi: 10.1016/j.molcel.2009.12.024.
The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways.
NEDD8 激活酶 (NAE) 启动了一种对癌细胞生长和存活至关重要的蛋白质动态平衡途径。MLN4924 是一种 NAE 的选择性抑制剂，目前正在临床试验中用于癌症治疗。在这里，我们表明 MLN4924 是 NAE 的一种基于机制的抑制剂，并在酶的催化下产生了一种共价的 NEDD8-MLN4924 加合物。该 NEDD8-MLN4924 加合物类似于 NAE 反应循环中的第一个中间产物 NEDD8 腺苷酸，但不能在后续的酶内反应中进一步利用。该 NEDD8-MLN4924 加合物在 NAE 活性位点内的稳定性阻断了酶的活性，从而解释了 MLN4924 对 NEDD8 途径的强效抑制作用。重要的是，我们已经确定类似 MLN4924 的化合物具有与其他泛素样蛋白 (UBL) 形成类似加合物的能力，这些 UBL 由其同源激活酶催化。这些发现揭示了 E1s 的作用机制，并提出了一种用于选择性抑制 UBL 缀合途径的通用策略。
