subasumstat (TAK-981)

P1/2, N=161, Completed, Takeda | N=109 --> 161

Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth...Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of Tregs through innate immune cells, potentially by activation of type I interferon responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.

TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.

The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment.

We recently completed a clinical trial in dogs with DLBCL using a combination of canine anti-CD20 antibody and low dose doxorubicin followed by one of three small molecule immune-modulating agents (KPT-9274, TAK-981 or RV1001). To facilitate point-of-care PBMC gene expression testing that could be used to distinguish those dogs likely to require more intensive treatment regimens in advance of relapse, we developed qPCR assays for TBHD, NPNT and ISG20 . Together these data provide proof of principle that biomarker interrogation in PBMCs can help predict early relapse and poor responders to inform clinical management of DLBCL.

TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability...Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.

Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells...Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells.

SUMOylation inhibition using Subasumstat also led to altered nuclear stress bodies morphology but did not impair Hsp70 induction or enhance Hsp90 inhibitor cytotoxicity. Our findings reveal that SUMOylation is dispensable for HSF1 activation and transactivation capacity during the early phase of HSR. These results refine our understanding of HSF1 regulation and suggest that alternative strategies targeting HSF1 stability and degradation may enhance the therapeutic efficacy of proteostasis-targeting cancer therapies.

Its activity was effectively counteracted by TAK-981, a SUMO inhibitor that demonstrated significant therapeutic potential by suppressing RMS cell proliferation and migration, and enhancing the cytotoxic effects of chemotherapeutic agents actinomycin D and doxorubicin. The findings of this study establish TAK-981 as a promising therapeutic agent for RMS. The results also provide foundational insights into the role of SUMOylation associated with the new biomarker SAE1 in RMS and its subtypes, paving the way for the development of personalized treatment strategies that leverage SUMO pathway inhibition.

Notably, although TAK-981 enhances reactive oxygen species production, it also induces apoptosis through a reactive oxygen species-independent mechanism, as evidenced by increased apoptosis rates upon co-treatment with antioxidants such as N-acetylcysteine. Additionally, TAK-981 reduced extracellular matrix accumulation by suppressing Collagen I and Acta2 expression and promoted autophagy in ELT3 cells, as indicated by increased levels of LC3. These findings suggest that TAK-981 can be used as a therapeutic option for managing uterine leiomyomas through multiple mechanisms, including apoptosis induction and autophagy promotion.

We assessed SUMOylation expression patterns and function in PDAC using Western blot and the SUMOylation inhibitor TAK-981...This study underscores the role of SUMOylation in PDAC and introduces the Sscore as a prognostic tool. SAFB2 is identified as a potential tumor suppressor, offering new therapeutic targets for PDAC.

P1/2, N=109, Completed, Takeda | Active, not recruiting --> Completed | N=49 --> 109 | Trial completion date: Nov 2025 --> Oct 2024 | Trial primary completion date: Nov 2025 --> Oct 2024