Subasumstat

Subasumstat is a selective inhibitor of the SUMOylation enzyme cascade with potent anti-leukemic activity^[1]. SUMOylation is a reversible post-translational modification that is involved in the regulation of multiple cellular processes, including inflammatory responses and type 1 interferon (IFN1) expression^[2]. Subasumstat can induce the expression of natural killer cell (NK cell) ligands on acute myeloid leukemia cells and activate NK cell cytotoxicity^[3].

In vitro, treatment of human NK cells with Subasumstat (1μM) for 24h significantly increased the intracellular mRNA expression of interferon-γ-induced protein 10 (IP-10) and cluster of differentiation 69 (CD69)^[4]. Subasumstat (1μM) treatment of T cells from patients with chronic lymphocytic leukemia (CLL) significantly reduced regulatory T cell (Treg) differentiation and induced IFNγ secretion by CD4⁺ and CD8⁺ T cells^[5].

In vivo, Subasumstat (15mg/kg) was treated intravenously in THP-1 xenograft mice, which significantly inhibited tumor progression in mice, prolonged the survival of mice, and exerted a synergistic effect with 5-azacytidine (AZA)^[6]. Subasumstat (25mg/kg) was treated intravenously in multiple myeloma (MM) cell xenograft mice for 7 days, which significantly inhibited tumor growth and induced apoptosis of primary MM cells^[7].

References:
[1] Kotani H, Oshima H, Boucher J C, et al. Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage[J]. Journal of Biomedical Science, 2024, 31(1): 68.
[2] Du L, Liu W, Rosen S T, et al. Mechanism of SUMOylation-mediated regulation of type I IFN expression[J]. Journal of Molecular Biology, 2023, 435(5): 167968.
[3] Hallal R, De Toledo M, Tempe D, et al. The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias[J]. bioRxiv, 2024: 2024.02. 19.580882.
[4] Nakamura A, Grossman S, Song K, et al. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation[J]. Blood, The Journal of the American Society of Hematology, 2022, 139(18): 2770-2781.
[5] Lam V, Roleder C, Liu T, et al. T cell–intrinsic immunomodulatory effects of TAK-981 (subasumstat), a SUMO-activating enzyme inhibitor, in chronic lymphocytic leukemia[J]. Molecular cancer therapeutics, 2023, 22(9): 1040-1051.
[6] Gabellier L, De Toledo M, Chakraborty M, et al. SUMOylation inhibitor TAK-981 (subasumstat) synergizes with 5-azacytidine in preclinical models of acute myeloid leukemia[J]. Haematologica, 2023, 109(1): 98.
[7] Heynen G J J E, Baumgartner F, Heider M, et al. SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma[J]. Blood Advances, 2023, 7(4): 469-481.

Subasumstat是一种SUMOylation 酶联反应的选择性抑制剂，具有有效的抗白血病活性^[1]。SUMOylation是一种可逆的翻译后修饰，参与多种细胞过程的调节，包括炎症反应和1型干扰素（IFN1）的表达^[2]。Subasumstat能够在急性髓样白血病细胞上诱导自然杀伤细胞（NK细胞）配体的表达，并激活NK细胞的细胞毒性^[3]。

在体外，Subasumstat（1μM）处理人NK细胞24h，显著提高了细胞内γ干扰素诱导蛋白10（IP-10）和分化抗原簇69（CD69）的mRNA表达^[4]。Subasumstat（1μM）处理来自慢性淋巴细胞白血病（CLL）患者的T细胞，显著减少了调节性T细胞（Treg）分化，诱导了CD4⁺和CD8⁺ T细胞分泌IFNγ^[5]。

在体内，Subasumstat（15mg/kg）通过静脉注射治疗THP-1异种移植小鼠，显著抑制了小鼠体内的肿瘤进展，延长了小鼠的生存期，并与5-azacytidine（AZA）发挥协同效应^[6]。Subasumstat（25mg/kg）通过静脉注射治疗多发性骨髓瘤（MM）细胞异种移植小鼠7天，显著抑制了肿瘤生长，诱导了原代MM细胞凋亡^[7]。