TAK-243 / Takeda, Ligand - LARVOL DELTA

TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The ubiquitin-activating enzyme inhibitor TAK-243 activates store-operated Ca2+ channels independently of endoplasmic reticulum Ca2+ stores and enhances mitochondrial Ca2+ buffering capacity in DU-145 human prostate cancer cells. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Live-cell Ca2+ imaging with Fura2 showed that DU-145 cells exhibited spontaneous Ca2+ transients that were largely independent of the activity of the Na+/Ca2+ exchanger but were abolished by extracellular Ca2+ removal, La3+, Gd3+, BTP2 (Orai channel blocker), and thapsigargin (which depletes endoplasmic reticulum -ER- Ca2+ stores). They were also sensitive to U73122 (a phospholipase C inhibitor) and dantrolene (a ryanodine receptor blocker), suggesting the contribution of both store-operated Ca2+ channels and intracellular Ca2+ release pathways in the generation and maintenance of these Ca2+ spikes...TAK-243 also increased the membrane potential and the Ca2+ buffering capacities of mitochondria. Taken together, treating DU-145 cells with TAK-243 to prevent the ubiquitination of proteins activates the entry of Ca2+ through store-operated Ca2+ channels independently of the ER Ca2+ stores and alters mitochondrial functions."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • STIM1

TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

VEXAS Patient Neutrophils Display a Dysregulated Immune Response and an Increase in Immature Neutrophil Populations. (EULAR 2026) - "Using the UBA1 inhibitor TAK-243 we were able to directly link reduction in UBA1 activity to a reduction in ROS generation in THP1 cells...(C) The percentage of neutrophils that were classified as immature, due to low CD10 expression. Asterisks indicate significance (p<0.05) as determined by ANOVA."

Clinical • Aplastic Anemia • Hematological Disorders • Infectious Disease • Inflammation • Targeted Protein Degradation • CXCL8 • CXCR2 • CXCR4 • GLI2 • MME

UBA1 drives cell cycle to promote malignancy and serves as a therapeutic target in Ewing Sarcoma. (PubMed, BMC Cancer) - "Targeting UBA1 disrupts cell cycle progression and inhibits proliferation in ES, underscoring its therapeutic potential."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation

Unexpected ribosome turnover during prolonged translation inhibition. (PubMed, bioRxiv) - "Upon testing inhibitors of both pathways, only proteasome inhibitors (i.e., MG132 and bortezomib) rescued both rRNA and ribosomal protein levels...Remarkably, rRNA levels were not rescued during CHX treatment when co-treated with the Ub activating enzyme E1 inhibitor, TAK243...Proteasome-dependent turnover of rRNA was also observed with high doses of other elongation inhibitors, namely anisomycin, homoharringtonine, and lactimidomycin. The recognition capabilities of the pathway were further expanded as we observed that 80S ribosomes not trapped on the mRNA were also targeted for degradation by the proteasome. Together, our findings define the framework of a regulatory pathway in mammalian cells that degrades both ribosomal subunits in response to prolonged periods of robust elongation inhibition."

Journal • Infectious Disease • Targeted Protein Degradation

TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts (clinicaltrials.gov) - P1 | N=42 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

NPP-2-21: A rationally designed prodrug of a UBA1 inhibitor with improved pharmacologic properties and antitumor activity (AACR 2026) - "However, the clinical development of the first-in-class UBA1 inhibitor TAK-243 is constrained by its limited patent lifespan, creating a need for next-generation UBA1-targeting agents...Notably, NPP-2-21 is compatible with liposomal formulation, enabling a reduction in dosing frequency from six to three doses over two weeks without loss of efficacy or increased toxicity. Collectively, these findings establish NPP-2-21 as a promising translational candidate for UBA1-directed cancer therapy."

Late-breaking abstract • Oncology

Small-molecule stabilization of non-native c-Myc multimer drives degradation using an IDP-targeting discovery platform (AACR 2026) - "Our hit RDP-02004 induced rapid, dose-dependent loss of c-Myc protein (DC₅₀ ~5-10 µM) and apoptosis across diverse MYC-dependent cancer cell lines, including multiple myeloma, lung and triple-negative breast cancer, with selectivity over non-transformed cells...The proteasome inhibitor MG-132, the ubiquitin-activating enzyme inhibitor TAK-243, and the autophagy inhibitor Autophinib each rescued c-Myc levels after compound treatment, implicating both ubiquitin-proteasome and aggrephagy-like mechanisms...Structure-activity and pharmacophore analyses, together with structure-based design, yielded additional series with improved properties and activity (DC₅₀ < 1 µM). These data provide proof of concept that exploiting IDP conformational ensembles to stabilize degradable c-Myc assemblies can generate small-molecule c-Myc degraders and support further optimization of this platform toward safer, more selective anti-MYC therapeutics."

Breast Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • Triple Negative Breast Cancer • MYC • SDC1

Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168. (PubMed, Res Sq) - "DUB inhibitors such as VLX-1570 promote ubiquitin-dependent enrichment of SLFN11 without detectable DNA damage, distinct from the camptothecin-induced RPA-associated SLFN11 foci formed at stressed replication forks. Yet, SLFN11 chromatin recruitment both by DUB inhibitors and DNA damage are suppressed by TAK243 demonstrating their ubiquitylation dependency. RNF168 is required for SLFN11 ubiquitylation and its subsequent chromatin association, and ubiquitylation within SLFN11's middle linker domain (lysines 390, 391, and 429) with K27-linked polyubiquitin chains is essential for the chromatin recruitment of SLFN11. These findings suggest the importance of SLFN11 ubiquitylation by RNF168 for SLFN11 chromatin recruitment and SLFN11 transcriptional regulatory role at promoter regions."

Journal • Oncology • Targeted Protein Degradation • RNF168 • SLFN11

Studying TAK-243 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=95 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2026 ➔ Apr 2027 | Trial primary completion date: Apr 2026 ➔ Apr 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation

Revolutionizing cancer treatment with the first SHP2 PROTAC (AACR 2025) - "SHP2 inhibitors, like JAB3312, is limited to inhibiting phosphatase activity and evaluated in combination regimens rather than as standalone therapies...Mechanistic studies confirmed TRD209 acts via ubiquitin-proteasome pathway, as validated by TAK-243 and MG132 blockade assays...TDS0593 offer a novel strategy for the treatment of myeloid leukemia by correcting aberrant myeloid-biased differentiation of HSC/HSPC. This innovative approach aims to rectify the underlying dysregulation in hematopoietic differentiation processes, achieving efficacy in myeloid leukemia.TDS0593 reduces leukemic burden and promotes the restoration of HSC% of Myeloid cells in BM% of Myeloid cells in PBHSC/45.2+ in BMnaive48.72(39.47~52.37)40.16(37.27~43.06)0.00312(0.00257~0.004635)kras-mut mouse models + vehicle66.50(64.40~69.40)59.40(41.00~72.10)0.01079(0.007630~0.01500)kras-mut mouse models + TDS059354.07(47.60~63.20)38.32(29.10~51.30)0.005865(0.002350~0.009110)"

IO biomarker • Late-breaking abstract • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • KRAS • PD-1 • PTPRC

Ubiquitin-dependent recruitment of SLFN11 to chromatin is regulated by deubiquitinase (DUB) and RNF168. (PubMed, bioRxiv) - "DUB inhibitors such as VLX-1570 promote ubiquitin-dependent enrichment of SLFN11 without detectable DNA damage, distinct from the camptothecin-induced RPA-associated SLFN11 foci formed at stressed replication forks. Yet, SLFN11 chromatin recruitment both by DUB inhibitors and DNA damage are suppressed by TAK243 demonstrating their ubiquitylation dependency. RNF168 is required for SLFN11 ubiquitylation and its subsequent chromatin association, and ubiquitylation within SLFN11's middle linker domain (lysines 390, 391, and 429) with K27-linked polyubiquitin chains is essential for the chromatin recruitment of SLFN11. These findings suggest the importance of SLFN11 ubiquitylation by RNF168 for SLFN11 chromatin recruitment and SLFN11 transcriptional regulatory role at promoter regions."

Journal • Oncology • Targeted Protein Degradation • RNF168 • SLFN11

Dual Targeting of IDH2 and the Ubiquitin-Proteasome System Reveals a Functional Vulnerability in Breast Cancer Models. (PubMed, Cancers (Basel)) - " A panel of human and murine breast cancer cell lines was treated with the IDH2 inhibitor AGI-6780, alone or in combination with the proteasome inhibitor carfilzomib (CFZ) or the E1 ubiquitin-activating enzyme inhibitor TAK-243. Inhibition of IDH2 markedly enhances the cytotoxic effects of proteasome-targeting by disrupting metabolic-proteostatic balance and promoting apoptotic cell death. These findings identify a growth-inhibitory effect that may be leveraged to improve functional dependency in breast cancer, particularly in triple-negative breast cancer, which currently lacks efficient drug treatments."

Journal • Preclinical • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • CASP3 • IDH2

Pex6 and ubiquitination regulate topological remodeling of the peroxisomal membrane protein Pex14. (PubMed, J Biol Chem) - "Conversely, inhibition of ubiquitin activation using MLN-7243 prevented this reorientation, likely by blocking Pex5 ubiquitination and its subsequent extraction from the membrane. These findings support a model in which Pex14 undergoes reversible, ATP-dependent topological remodeling during Pex5 recycling, functioning as a molecular reset mechanism for the docking/translocation complex. Our study reveals an additional mechanism of regulation in peroxisomal protein import and highlights the coordinated roles of Pex6 and Pex5 ubiquitination in maintaining the structural organization of the translocation machinery."

Journal • Targeted Protein Degradation

Zebrafish Abcg2a mutant line as an in vivo model for evaluation of the interaction of Abcg2a with drugs and contaminants. (PubMed, Aquat Toxicol) - "Upon exposure to the model toxicants MLN7243 and mitoxantrone, the mutant larvae showed increased mortality compared to the wildtypes. The addition of the specific inhibitor Ko143 increased the mortality rate of the wildtype larvae to that of the mutants, indicating that the protective effect of Abcg2a had been abolished. The developed Abcg2a mutant line could be used as a reliable in vivo model in both pharmacology and ecotoxicology to further elucidate the function of Abcg2a in different tissues and cell compartments and to better understand the interaction of Abcg2a with different physiological or xenobiotic compounds."

Journal • Preclinical • ABCG2

Sensitivity to Targeted UBA1 Inhibition in a Myeloid Cell Line Model of Vexas Syndrome (ASH 2023) - "We find that loss of UBA1b is a cause of reduced polyubiquitination and renders Uba1M41L cells vulnerable to targeted UBA1 inhibition by TAK243. Our Uba1M41L knock-in cell line is a faithful model of VEXAS syndrome that will aid in the study of disease pathogenesis and the development of effective therapies."

Preclinical • Aplastic Anemia • Hematological Disorders • Inflammation • Targeted Protein Degradation • ANXA5 • CXCL10 • CXCL12 • CXCL9 • IL1B

Inhibition of Topors Ubiquitin Ligase Augments the Efficacy of DNA Hypomethylating Agents through DNMT1 Stabilization (ASH 2023) - "MDS-L and MOLM-13 cells expressing Cas9 were infected with an sgRNA lentiviral library containing 12,409 sgRNAs targeting 1,383 epigenetic factors and exposed to low-dose HMAs, decitabine (DAC) or azacitidine (AZA), for 14 days...Furthermore, an ubiquitination inhibitor TAK-243 as well as a SUMOylation inhibitor TAK-981 showed synergistic effect with HMAs through DNMT1 stabilization. These results suggested that they are likely to be promising therapeutic agents in clinical practice. Our findings unveil a novel mechanism of resistance to HMAs and provide an attractive therapeutic strategy for myeloid malignancies that interferes with resolution of DNA-DNMT1 crosslinks by targeting DNMT1 post-translational modification."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • DNMT1 • UHRF1

Characterization of E1 Ligase Dependencies in a Mutant-UBA1 Human Cell Model Reveals UBA6 As a Novel Therapeutic Target in Vexas Syndrome (ASH 2024) - "We utilized the UBA1-specific inhibitor, TAK-243, and phytic acid, an allosteric UBA6 inhibitor (Yuan et al, Nat Commun, 2022), to further interrogate the roles of E1 ubiquitin ligases in VEXAS syndrome...Furthermore, pretreatment with phytic acid specifically impaired the colony formation potential of MUT UBA1-M41V cells while no reduction in the colony formation was observed in WT UBA1-M41M cells. Taken together, these studies suggest that UBA6 activity is required to maintain UBA1 mutant cells and represents a novel therapeutic targeting strategy for the treatment of VEXAS syndrome."

Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • ATF4 • GLI2

Primary Hematopoietic Cells of Vexas Patients Are Highly Sensitive to Treatment with TAK-243 and Pevonedistat (ASH 2024) - "With our results we hypothesize that the application of targeted inhibitors of UBA1, such as TAK-243, or related pathway steps, such as neddylation with pevonedistat, creates a "synthetic lethality" in UBA1-mutated cells by reducing the remaining UBA1 activity to a non-viable level. Consequently, treatment with these substances selectively eradicates UBA1-mutated myeloid progenitor cells, which are the basis of the inflammatory disease and thus holds promise for effectively treating VEXAS patients."

Clinical • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CD34 • DNMT3A

Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome. (PubMed, Nature) - "Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner...Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link VEXAS pathogenesis with that of rarer monogenic autoinflammatory syndromes; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and support therapeutic targeting of the inflammatory cell death axis in VEXAS."

Journal • Hematological Disorders • Inflammation • Targeted Protein Degradation • CASP8

NTCP ubiquitination enables HBV infection. (PubMed, JHEP Rep) - "The global ubiquitination inhibitor TAK-243 was used to study effects on uptake and HBV infection in NTCPWT-HepG2 and HepaRG cells...In addition, a K at position 340 was identified as the main ubiquitination target of NTCP; ubiquitination-mediated endocytosis of NTCP at this position is likely to be the mechanism regulating HBV internalization. Thus, interfering with NTCP ubiquitination could provide a novel means to reduce HBV infection."

Journal • Hepatitis B • Infectious Disease • Targeted Protein Degradation

Primary CD34+ cells of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome are highly sensitive to targeted treatment with TAK-243. (PubMed, Br J Haematol) - No abstract available

Journal • CD34

UBIQUITINATION OF NTCP AT RESIDUE K340 IS A CRITICAL DETERMINANT FOR NTCP ENDOCYTOSIS AND HEPATITIS B VIRUS (HBV) INFECTIO (AASLD 2025) - "TAK-243 was used to assess global ubiquitination effects on uptake activity and HBV infection in NTCPWT HepG2 and HepaRG cells... The lysine residue at position 340 plays a crucial role in NTCP ubiquitination. Interfering with NTCP ubiquitination resulted in impaired NTCP endocytosis and a concomitant reduction in HBV infection. Our study directly shows that NTCP-mediated endocytosis is critical for HBV entry into the liver."

Hepatitis B • Hepatology • Infectious Disease • Inflammation • Targeted Protein Degradation

Ubiquitin-like post-translational modifications may modulate the pathogenesis of chronic lymphocytic leukemia mediated by RRAS2 (IWCLL 2025) - "In concordance with a protective function of NEDDylation against ubiquitin-proteasome degradation, the NEDD8-degrader enzyme NUB1 induced a reduction in RRAS2 protein accumulation, while the ubiquitin activator enzyme (UBA) inhibitor TAK243 stabilized the protein.In the CLL cell line MEC-1, RRAS2 protein decrease after Pevonedistat treatment came along with a down regulation of its mRNA., suggesting a possible additional regulation at the transcriptional level.Functionally, our data demonstrated a higher sensitivity of RRAS2-overexpressing MEC-1 cells to specific combinational treatments like Ibrutinib + Pevonedistat or Rohinitib + Pevonedistat, just as CLL cells do. MEC-1-RRAS2 cells exhibit higher mRNA expression of BCL2 and EIF4A1 as well as an increase in general RNA transcription. In addition, our preliminary data in HeLa cells show how Pevonedistat induces a redistribution of RRAS2 from the membrane to a more cytoplasmic location.ConclusionOur work suggests a..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • BCL2 • EIF4A1 • NUB1 • RRAS2