TAK-981 is a new small molecule inhibitor of sumoylation. Through intravenous administration, TAK-981 targets and covalently binds to the small ubiquitin-like modifier (SUMO; small ubiquitin-related modifier) protein, preventing SUMO conjugation to lysine residues on target proteins and abrogating many sumoylated protein-mediated cellular processes that play key roles in tumor cells, including proliferation, DNA repair, metastasis and survival. Through preventing sumoylation, TAK-981 is able to increase the production of type 1 IFN and thereby increases type 1 IFN-mediated signaling, activates innate effector cells and enhances the antitumor innate immune responses. This may further increase tumor cell killing. These suggest TAK-981 may have potential immune-activating and antineoplastic activities.
作用机制
TAK-981 could covalently bind to SUMO protein and form an adduct with SUMO protein, which prevents the transfer of SUMO from the SUMO-activating enzyme (SAE) to SUMO-conjugating enzyme UBC9.[1]
Subasumstat 细胞实验
Cell Line
Concentration
Treated Time
Description
References
OPM2 cells
250 nM
16 hours
Subasumstat treatment induced DNA repair and apoptosis signaling pathways in OPM2 cells.
Blood Adv. 2023 Feb 28;7(4):469-481.
T cells from patients with chronic lymphocytic leukemia (CLL)
1 µM
18 hours
To investigate the effect of TAK-981 on T cell activation, results showed that TAK-981 reduced the expression of SUMOylated proteins.
Mol Cancer Ther. 2023 Sep 5;22(9):1040-1051.
HL-60 cells
10 nM
24 hours
TAK-981 significantly reduced SUMOylation levels in HL-60 cells and showed synergistic cytotoxicity with AZA.
Haematologica. 2024 Jan 1;109(1):98-114.
U937 cells
10 nM
24 hours
TAK-981 significantly reduced SUMOylation levels in U937 cells and showed synergistic cytotoxicity with AZA.
Haematologica. 2024 Jan 1;109(1):98-114.
THP-1 cells
10 nM
24 hours
TAK-981 significantly reduced SUMOylation levels in THP-1 cells and showed synergistic cytotoxicity with AZA.
Haematologica. 2024 Jan 1;109(1):98-114.
WT iTreg cells
100 nM
24 hours
To investigate the effect of TAK981 on iTreg cells. Results showed that TAK981 treatment upregulated IFNAR1 and IFN γ, and decreased the expression of NRP1.
Cancer Immunol Res. 2022 Dec 2;10(12):1490-1505.
MCL cell lines
50 and 100 nM
3 days
Evaluate the effect of TAK-981 on MCL cell viability, showing significant reduction in viable cells in 7/8 cell lines
Exp Hematol Oncol. 2022 Jul 13;11(1):40.
Primary MCL patient samples
50 and 100 nM
3 days
Evaluate the effect of TAK-981 on primary MCL patient samples, showing significant reduction in viable cells in 4/5 samples
Exp Hematol Oncol. 2022 Jul 13;11(1):40.
JJN3 cells
250 nM
3 days
Subasumstat monotreatment significantly reduced the viability of JJN3 cells and showed synergy with the proteasome inhibitor CFZ.
Blood Adv. 2023 Feb 28;7(4):469-481.
Multiple KRAS-mutant human and mouse cancer cell lines
10 µM to 1.5 nM
72 hours
To evaluate the sensitivity of TAK-981 to KRAS-mutant cancer cells, the results showed that nearly 70% of the cell lines were sensitive to TAK-981, with IC50 values less than 1 µM.
J Biomed Sci. 2024 Jul 11;31(1):68.
Subasumstat 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD-SCID-gammaIL2Rnull (NSG) mice
Acute Myeloid Leukemia (AML) xenograft model
Intravenous (IV) and intraperitoneal (IP) injection
15 mg/kg
Once daily for 9 days
The combination of TAK-981 and AZA significantly inhibited tumor progression in the AML xenograft model and extended mouse survival.
Haematologica. 2024 Jan 1;109(1):98-114.
Mice
MC38 tumor model
Intravenous injection
15 mg/kg
Day 7 and Day 14
To investigate the effect of TAK981 on tumor growth and Treg cell status. Results showed that TAK981 significantly suppressed tumor growth and prolonged animal survival. The therapeutic efficacy of TAK981 was eliminated in mice lacking IFNAR1 on their Treg cells, suggesting that reactivation of the IFN1–IFNAR1 pathway in Treg cells contributes to the mechanism of action of TAK981.
Cancer Immunol Res. 2022 Dec 2;10(12):1490-1505.
C57BL/6J mice and CAnN.Cg-Foxn1nu/Crl-Crlj mice
Immunocompetent and immunodeficient mouse models
Intraperitoneal injection
25 mg/kg
Twice a week, continuous treatment
To evaluate the antitumor effect of TAK-981 in immunocompetent and immunodeficient mouse models, the results showed that TAK-981 significantly suppressed tumor growth, indicating that SUMOylation inhibition exhibited an immune-independent antitumor effect.
J Biomed Sci. 2024 Jul 11;31(1):68.
NOD.CB17/AlhnRj-PrkdcSCID/Rj mice
Multiple myeloma xenograft models
Intravenous
25 mg/kg
Twice per week for 7 days
Combination treatment of subasumstat and CFZ significantly inhibited tumor growth without observable side effects.
Blood Adv. 2023 Feb 28;7(4):469-481.
NSG mice
MCL xenograft models
Tail vein injection
7.5 mg/kg
Twice weekly, until the end of the experiment
Evaluate the anti-tumor activity of TAK-981 in MCL xenograft models, showing significant extension in median survival of mice
Exp Hematol Oncol. 2022 Jul 13;11(1):40.
Mice
A20 B-cell lymphoma model
Intravenous injection
7.5 mg/kg
Days 1, 4, 7, and 11
To investigate the effect of TAK-981 on the A20 lymphoma model, results showed that TAK-981 delayed tumor growth.
Mol Cancer Ther. 2023 Sep 5;22(9):1040-1051.
Mice
Sepsis models (CLP and LPS endotoxemia)
Subcutaneous injection
7.5 mg/kg
Every 24 hours for 4 days
TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. TAK981 also increased early TNFα production but did not affect the resolution of inflammation.
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