TAK-243 (MLN7243)

TAK-243 (MLN7243) is a selective inhibitor of ubiquitin activating enzyme (UBA1) with an IC₅₀ value of 1nM^[1]. TAK-243 can block ubiquitin binding, disrupt monoubiquitin signaling and global protein ubiquitination, and is currently used as an anticancer drug in clinical trials^[2]. TAK-243 can induce endoplasmic reticulum stress (ERS) response, eliminate NF-κB pathway activation, and promote cell apoptosis^[3].

In vitro, TAK-243 (0-1000nM) treatment of SLFN11 wild-type (WT) and SLFN11 knockout (KO) prostate cancer DU145, hepatocellular carcinoma Li-7 and leukemia MOLT4 cells for 72h inhibited cell viability in a concentration-dependent manner. SLFN11-KO cells were significantly more sensitive to TAK-243 than their WT counterparts^[4]. TAK-243 (0-100nM) was used to treat multiple myeloma cell lines (MM1.S and MOLP-8 TP53 wild-type cells) for 24h, with an IC₅₀ value of approximately 25nM, which significantly increased the levels of intracellular cleaved caspase-3, -8, and -9 and reduced the content of ubiquitin-protein conjugates^[5].

In vivo, TAK-243 (10, 20mg/kg) was used to treat H295R cell xenograft mice by intraperitoneal injection for 29 days, which significantly inhibited tumor growth, reduced the expression level of ubiquitinated proteins in tumor tissues, and induced tumor cell apoptosis^[6]. TAK-243 (20mg/kg) was used to treat acute myeloid leukemia (AML) cell xenograft mice by subcutaneous injection for 3 weeks, which reduced the AML tumor burden and the levels of monoubiquitinated and polyubiquitinated proteins in tumor tissues^[7].

References:
[1] Hyer M L, Milhollen M A, Ciavarri J, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment[J]. Nature medicine, 2018, 24(2): 186-193.
[2] Best S, Hashiguchi T, Kittai A, et al. Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells[J]. Blood advances, 2019, 3(1): 51-62.
[3] Wang G, Fan F, Sun C, et al. Looking into endoplasmic reticulum stress: the key to drug-resistance of multiple myeloma?[J]. Cancers, 2022, 14(21): 5340.
[4] Murai Y, Jo U, Murai J, et al. SLFN11 inactivation induces proteotoxic stress and sensitizes cancer cells to ubiquitin activating enzyme inhibitor TAK-243[J]. Cancer research, 2021, 81(11): 3067-3078.
[5] Zhuang J, Lee H, Kuiatse I, et al. The anti-tumor effect of the ubiquitin-activating enzyme (UAE) inhibitor TAK-243 on pre-clinical models of multiple myeloma[J]. 2016.
[6] Arakawa Y, Jo U, Kumar S, et al. Activity of the ubiquitin-activating enzyme inhibitor TAK-243 in adrenocortical carcinoma cell lines, patient-derived organoids, and murine xenografts[J]. Cancer Research Communications, 2024, 4(3): 834-848.
[7] Barghout S H, Patel P, Wang X, et al. TAK-243 is a selective UBA1 inhibitor that displays preclinical activity in acute myeloid leukemia (AML)[J]. Blood, 2017, 130: 814.

TAK-243 (MLN7243)是一种选择性泛素活化酶（UBA1）抑制剂，IC₅₀值为1nM^[1]。TAK-243能够阻断泛素结合，破坏单泛素信号传导和全蛋白泛素化，目前在临床试验中作为抗癌药物使用^[2]。TAK-243能够诱导内质网应激（ERS） 反应，消除 NF-κB通路活化，促进细胞凋亡^[3]。

在体外，TAK-243（0-1000nM）处理SLFN11野生型（WT）和SLFN11敲除（KO）前列腺癌DU145、肝细胞癌Li-7和白血病MOLT4细胞72h，以浓度依赖性方式抑制了细胞活力，SLFN11-KO细胞对TAK-243的敏感性明显高于其WT对应细胞^[4]。TAK-243（0-100nM）处理多发性骨髓瘤细胞系（MM1.S和MOLP-8 TP53野生型细胞）24h，IC₅₀值约为25nM，显著增加了细胞内裂解的caspase-3、-8和-9水平，降低了泛素-蛋白质结合物的含量^[5]。

在体内，TAK-243（10, 20mg/kg）通过腹腔注射治疗H295R细胞异种移植小鼠29天，显著抑制了肿瘤生长，减少了肿瘤组织在泛素化蛋白质表达水平，诱导了肿瘤细胞凋亡^[6]。TAK-243（20mg/kg）通过皮下注射治疗急性髓细胞性白血病（AML）细胞异种移植小鼠3周，降低了AML肿瘤负担，降低了肿瘤组织中单泛素化和多泛素化蛋白的水平^[7]。