TAK-243 / Takeda, Ligand - LARVOL DELTA

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

Pevonedistat Enhances the Cytotoxic Effect of Rohinitib on B Cells of Chronic Lymphocytic Leukemia (IWCLL 2025) - "An inhibitor of NEDDylation, Pevonedistat, has shown a cytotoxic effect on CLL cells, and results from a clinical study in combination with Ibrutinib have recently been published.Objective The aim of this work is to study the effect of the combined inhibition of RNA translation and NEDDylation on CLL and analyze its mechanism to provide information on the molecular causes of this pathology.Methods We analyzed the cytotoxicity of a translation inhibitor (Rohinitib) and a NEDDylation inhibitor (Pevonedistat) on B cells from CLL patients treated ex vivo, using analysis of 7-AAD staining by flow cytometry, as well as by oxidation of tetrazolium salts (XTT)...Moreover, this effect appears to be specific to direct NEDDylation, as the same synergy is not observed with the ubiquitination inhibitor, TAK-243...Our data showed a cooperative effect of these drugs in the inhibition of BCL2 and the activation of TP53, suggesting their mediation in the synergistic induction of..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • BCL2 • EIF4A1 • LYN • PDCD4 • SYK

PPM1D is directly degraded by proteasomes in a ubiquitination-independent manner through its carboxyl-terminal region. (PubMed, J Biomed Sci) - "The rapid degradation of the cancer driver PPM1D is achieved through direct recognition by the proteasome, and proteasome inhibitors may reduce therapeutic efficacy due to the accumulation of PPM1D. PPM1D may serve as a suitable model substrate for elucidating the mechanism of ubiquitin-independent proteasomal degradation and represents a potential novel therapeutic target for cancer treatment based on proteasome inhibition."

Journal • Oncology • Targeted Protein Degradation • PPM1D • PSMD14

SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms. (PubMed, Leukemia) - "UBA1 mis-splicing (UBA1ms) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243...In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments."

Journal • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CD34 • SF3B1

SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation. (PubMed, Cell Death Dis) - "In contrast, blocking ubiquitination or NEDDylation, with TAK-243 or MLN4924/Pevonedistat respectively, increases p14ARF SUMOylation and restores p14ARF levels when SUMOylation is blocked. Finally, p14ARF contributes to MLN4924-driven cytotoxicity of prostate cancer cells. Our results provide evidence that, despite lacking lysine, p14ARF is SUMOylated and this modification is critical to counter ubiquitin driven degradation and establishes a new link between inhibition of NEDDylation and SUMOylation."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CDKN2A • UBE2I

Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome. (PubMed, Leukemia) - "Treatment with the E1 enzyme inhibitor TAK-243 preferentially suppressed colony formation of UBA1M41V cells as compared to WT cells...Phytic acid selectively impaired growth and colony formation in UBA1M41V cells while sparing WT cells, highlighting a potential therapeutic vulnerability. Together, these findings establish a novel human model of VEXAS syndrome, identify key roles for UBA1 and UBA6 in disease pathogenesis, and demonstrate that UBA6 inhibition represents a promising therapeutic strategy for selectively targeting UBA1 mutant clones."

Journal • Aplastic Anemia • Hematological Disorders • Inflammation • Targeted Protein Degradation • GLI2

H. Influenzae Type B Infection Stabilizes an Immune Suppressor Protein, FBXO24 (ATS 2025) - "THP-1 cells treated with the E3 ligase inhibitor (MLN-7243), the proteasome inhibitor (MG-132), and a lysosomal inhibitor (Baf-A1), showed that degradation of FBXO24 occurs via the endo-lysosomal degradation pathway. These data suggest that a common respiratory pathogen increases abundance of a relatively newly described E3 ligase protein by altering its rate of ubiquitin-mediated degradation. The results present a unique mechanism whereby a pathogen can exploit host responses thereby impairing innate immune responses observed in bacterial pneumonia."

Infectious Disease • Influenza • Pneumonia • Respiratory Diseases • Targeted Protein Degradation

Ubiquitin-activating enzyme1 (TgUAE1) acts as a key regulator of Toxoplasma gondii lytic cycle and homeostasis. (PubMed, Commun Biol) - "TAK-243, a UAE1 inhibitor, can effectively inhibit the ubiquitin pathway in T. gondii, as thermal stabilization experiments identified TgUAE1 as its intracellular target...Transcriptomics and quantitative ubiquitin proteomics revealed TgUAE1 as a key regulator of the ubiquitination process and the broader gene expression network in T. gondii. These findings not only underscore the indispensable role of TgUAE1 in the life cycle of T. gondii but also offer valuable data that could inform future studies on parasite biology and the development of novel therapeutic strategies."

Journal • 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

MED10 Increases Cisplatin Resistance by Promoting PTEN Ubiquitination of Hepatocellular Carcinoma. (PubMed, Curr Cancer Drug Targets) - "MED10 enhances cisplatin resistance by promoting PTEN ubiquitination in HCC cells."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PTEN

Novel Functions of TRIM21: Post-Translational Regulation of Cytoplasmic Antiretroviral APOBEC3s (CROI 2025) - "Transfection models were used to characterize the domains of TRIM21 required for activity and if a CRL was needed by using an inhibitor of cullin-activating neddylation (MLN4924) or monoubiquitination (TAK-243). TRIM21 regulation of the A3s is present in physiologically relevant cell models and requires CRL ubiquitination. TRIM21 knockdown reduces HIV production, suggesting future efforts to discover a TRIM21 inhibitor that limits spread of HIV."

Human Immunodeficiency Virus • Infectious Disease • Targeted Protein Degradation • APOB • TRIM21

A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity. (PubMed, Sci Adv) - "We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated "free" phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation

Ubiquitin-like modifier-activating enzyme 1 as a potential therapeutic target for aortic dissection. (PubMed, Int Immunopharmacol) - "Treatment of TAK-243, a specific UBA1 inhibitor, prevented BAPN-induced AD formation in mice and attenuated aortic medial degeneration, as evidenced by decreased elastin fragmentation (evaluated by EVG scoring), reduced vascular smooth muscle cell loss (visualized by α-SMA immunohistochemistry), and less extracellular matrix degradation (indicated by diminished MMP2 and MMP9 expression in immunohistochemistry and RT-qPCR)...In conclusion, we demonstrate that UBA1 may facilitate AD progression by promoting macrophage activation via the NF-κB signaling pathway. These findings reveal a pathogenic role for the E1 enzyme UBA1 in AD and show a pharmacological potential of UBA1-targeted therapy against this disease."

Journal • Targeted Protein Degradation • CD68 • MMP2 • MMP9 • NFKBIA

The UBA1-STUB1 axis mediates cancer immune escape and resistance to checkpoint blockade. (PubMed, Cancer Discov) - "Importantly, a selective UBA1 inhibitor, TAK-243, significantly synergized with ICB in multiple syngeneic models. Mechanistically, depletion or inactivation of the UBA1-STUB1 axis stabilized a key interferon pathway component (JAK1), enhanced IFN-signaling, and elevated key immune modulators, including CXCL9, CXCL10, and MHC class I. Our study warrants clinical evaluation of the combination of UBA1 inhibitors and ICB."

Checkpoint block • Checkpoint inhibition • Journal • Oncology • Targeted Protein Degradation • CD8 • CXCL10 • CXCL9 • JAK1

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) | Not yet recruiting ➔ Recruiting | N=72 ➔ 42 | Trial completion date: Dec 2024 ➔ Oct 2026 | Trial primary completion date: Dec 2024 ➔ Oct 2026

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD4

AAMP and MTSS1 Are Novel Negative Regulators of Endothelial Barrier Function Identified in a Proteomics Screen. (PubMed, Cells) - "Following short-term inhibition of ubiquitination with E1 ligase inhibitor MLN7243 or Cullin E3 ligase inhibitor MLN4924 in primary human endothelial cells, we identified sixty significantly differentially expressed proteins. Mechanistically, AAMP regulates the stability and activity of RhoA and RhoB, and colocalizes with F-actin and cortactin at membrane ruffles, possibly regulating F-actin dynamics. Taken together, these findings demonstrate the critical role of protein turnover of specific proteins in the regulation of endothelial barrier function, contributing to our options to target dysregulation of vascular permeability."

Journal • Targeted Protein Degradation • CTTN • MTSS1 • RHOA

TAK-243 and Pevonedistat as targeted therapy for patients with VEXAS syndrome (DGHO 2024) - "The IC50 value determined for CD34+ cells treated with TAK-243 was 22.57 nM for VEXAS patients, 133 nM for patients with MDS, and 192 nM for hematologically healthy individuals. For pevonedistat, the IC50 was 561 nM for VEXAS, 1048 nM for MDS and 1100 nM for HY CD34+ cells. Comparison of the IC50 value of VEXAS with MDS and HY samples for both TAK-243 and pevonedistat revealed significantly increased sensitivities of VEXAS samples (p≤0.0001 for all comparisons) to both treatments."

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