TAK-243 / Takeda, Ligand - LARVOL DELTA

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

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

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

Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor: Aryl-hydrocarbon receptor antagonist drug combinations. (PubMed, SLAS Discov) - "This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials...All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor...The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib."

Journal • Colon Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation

CFTR-F508del is targeted for endolysosomal degradation in the presence of small-molecule correctors (NACFC 2024) - " We performed a CRISPR/Cas9 KO screen with sublibrary against ~2,000 genes in the ubiquitin, autophagy, and lysosomal degradation pathways to identify machinery that targets CFTR-F508del in the presence of two correctors, elexacaftor and tezacaftor, that are principal components of CF drug therapy. Corrected CFTR-F508del was fully stabilized by treatment with TAK-243, a potent, selective inhibitor of ubiquitin activation, indicating that its degradation is mediated exclusively by ubiquitin-dependent pathways operating in both endoplasmic reticulum and post-endoplasmic reticulum compartments... Our data suggest that development of pharmacological inhibitors against the endolysosomal system can enhance the efficacy of current CF therapeutics."

Cystic Fibrosis • Dyslipidemia • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation

Studying TAK-243 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=95 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial completion date: May 2027 ➔ Apr 2026 | Initiation date: Aug 2024 ➔ May 2025 | Trial primary completion date: May 2027 ➔ Apr 2026

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

Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization. (PubMed, Nat Commun) - "Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Targeted Protein Degradation • DNMT1

Studying TAK-243 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=95 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2024 ➔ May 2027 | Initiation date: Apr 2024 ➔ Aug 2024 | Trial primary completion date: May 2024 ➔ May 2027

Metastases • Trial completion date • Trial initiation date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation

Human coronavirus NL63 nsp1 induces degradation of RNA polymerase II to inhibit host protein synthesis. (PubMed, PLoS Pathog) - "This degradation was detected regardless of the phosphorylation state of Rpb1 and was blocked by the proteasome inhibitor MG132. We also found that Rpb1 was ubiquitinated in NL63-infected cells, and inhibition of ubiquitination by a ubiquitin activating enzyme inhibitor (TAK243) prevented degradation of Rpb1 in virus-infected cells. These data reveal an unrecognized strategy of host shutoff by human α-CoV NL63: targeting host transcription by inducing Rpb1 degradation to prevent host protein expression. Our study indicates that viruses within the same family can use completely distinct mechanisms to regulate host antiviral responses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation

Activity of the ubiquitin-activating enzyme inhibitor TAK-243 in adrenocortical carcinoma (ACC) cell lines, patient-derived organoids (PDOs) and murine xenografts. (PubMed, Cancer Res Commun) - "Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids...These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage adrenocortical carcinoma. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors."

IO biomarker • Journal • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ABCB1 • SLFN11

Studying TAK-243 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=95 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Metastases • New P1 trial • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation

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 Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • Transplantation • DNMT1 • UHRF1

Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome. (PubMed, Blood Adv) - "Uba1M41L cells were more sensitive to the UBA1 inhibitor TAK243...Altogether, these data indicate that loss of UBA1b underlies a key biochemical phenotype associated with VEXAS syndrome and renders cells with reduced UBA1 activity vulnerable to targeted UBA1 inhibition. Our Uba1M41L knock-in cell line is a useful model of VEXAS syndrome that will aid in the study of disease pathogenesis and the development of effective therapies."

Journal • Preclinical • Aplastic Anemia • Hematological Disorders • Inflammation • Targeted Protein Degradation • IL1B

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

The ubiquitin-proteasome pathway inhibitor TAK-243 has major effects on calcium handling in mammalian cells. (PubMed, Biochim Biophys Acta Mol Cell Res) - "These effects correlated with induction of ER stress, and most seemed to be underpinned by enhanced Ca leak from the ER. Overall, these data indicate that TAK-243 reprograms the Ca-handling properties of mammalian cells and that these effects should be considered when UPP inhibitors are employed as therapeutic agents."

Journal • Oncology • Targeted Protein Degradation