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.