Abstract Ubiquitin-conjugating enzymes (E2s) govern ubiquitin chain topology and flux through the ubiquitin-proteasome system, thereby shaping proteostasis, DNA-damage responses, and oncogenic signaling. Although targeted protein degradation (TPD) has largely focused on E3 ligases, convergent evidence from recent chemical biology and oncology studies indicates that E2s are druggable nodes with dual therapeutic potential for reprogramming using bifunctional and molecular glue degraders. Here, we demonstrate that E2s can act as a recruitment engine for proximity-induced degradation when E3 access or cooperativity is limiting for a distinct set of targets. We introduce a first-in-class, selective, small-molecule-based bifunctional degrader platform that exploits E2 recruitment to degrade oncology-relevant targets, including nuclear receptors and kinases. In biochemical and cellular systems, the ligand engages its E2 target with high selectivity, induces proximity through ternary complex formation and degrades the protein of interest in a proteasome- and Cullen-dependent manner. We validated our approach by designing bifunctional degraders of ERα, coupling ERα and E2 ligands with short linkers, and demonstrating target degradation in MCF7, T47D, SH-SY5Y, and K562 cell lines. We demonstrate early degradation by 6 hours and maximal degradation at 24 hours with a Dmax of 85% and DC50 of 83nM. Further, by conjugating 4 kinase inhibitor scaffolds with 2-6 linker designs, we screened the proteome to cover almost 500 potential kinase targets in K562 and MCF7. We demonstrated dose-dependent degradation of dozens of kinases, including kinases of potential therapeutic interest such as SYK, FYN, and MAPK2. We observed dramatically different sensitivity to degradation across the cell lines tested, and degradation activity was more robust at the 24h timepoint compared to 5h. Collectively, these findings validate E2 ligases as functional recruiters for TPD, expanding the degrader toolbox beyond canonical E3 ligases and establishing a complementary, generalizable framework for therapeutic development. Citation Format: Xiangrong Chen, Vittorio Katis, Qilong Wu, Lukas Scheibelberger, Jesper Hansen, Brian D. Dill, Oksana Zavidji, Maria-Dorothea Nastke, Tiffany V. Saunders, Clifford G. Phaneuf, Andrea Pierangelini, Darragh O'Brien, Alejandro Gonzalez Orta, Niven R. Narain, Stephane Gesta, Alex N. Bullock, Dinesh Chimmanamada, Paul Brennan, Kilian Huber, Vivek K. Vishnudas. Leveraging E2 ligases for induced proximity and modulation of novel cancer-relevant targets and neosubstrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5794.

Primary coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder caused by mutations in genes involved in CoQ biosynthesis (e.g., COQ4) that result in impaired mitochondrial respiration, oxidative stress, and dysfunction across multiple organ systems because of decreased mitochondrial levels of CoQ10. Although oral CoQ10 supplementation has been examined for standard of care, poor absorption and inadequate tissue and intracellular distribution have resulted in a lack of clinically significant efficacy. BPM31510 is a lipid nanoparticle containing oxidized CoQ10 designed to improve bioavailability and targeted uptake into the mitochondria. In the current study, we assessed the efficacy of BPM31510 to increase CoQ levels in Coq4F147C mice, a novel genetic knock-in model of primary CoQ deficiency. Coenzyme Q9, the main form of CoQ in mice, and CoQ10 were significantly decreased in the brain, kidney, heart, and muscle of Coq4F147C mice compared with Coq4+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MS imaging demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4F147C mice. These results demonstrate that BPM31510 successfully concentrates pharmacologically active CoQ10 in target tissues that are not reachable with oral therapy in a genetic model of primary CoQ deficiency. We enabled the visualization of suborgan CoQ10 localization to specifically demonstrate CoQ10 restoration. This study establishes proof of concept for spatial quinomics, a new methodology that combines spatial metabolomics with quinomics to evaluate next-generation CoQ10-based therapeutics for mitochondrial disorders.

Coenzyme Q10 (CoQ10) is a lipid-soluble redox cofactor essential for mitochondrial electron transport, membrane stabilization, and antioxidant defense in its reduced form. Broad clinical utility has been hampered by poor oral bioavailability and low tissue uptake using nutraceutical formulations. BPM31510 is a novel pharmaceutical nanotechnology formulated with oxidized CoQ10 as a lipid nanoparticle designed to enhance systemic exposure and mitochondrial concentration. Using UHPLC-MS/MS, we quantified oxidized CoQ10, reduced CoQ10, and oxidized CoQ9 in BPM31510- and CoQ10-treated SH-SY5Y neuroblastoma cells following para-aminobenzoic acid (PABA)-induced CoQ deficiency. BPM31510 significantly increased all three analytes and raised ATP content in SH-SY5Y cells more effectively than solubilized CoQ10. In patient-derived fibroblasts with PDSS2, COQ2, or COQ8A mutations, BPM31510 outperformed nutraceutical formulations in enriching CoQ10 levels. In vivo, C57BL/6J mice received BPM31510 (10 or 50 mg/kg, intraperitoneal) or oral CoQ10 twice daily for 14 days. BPM31510 substantially increased oxidized and reduced CoQ10 in plasma, liver, heart, and adipose tissue, enhancing the overall CoQ pool relative to oral CoQ10. MALDI mass spectrometry imaging confirmed oxidized CoQ10 accumulation in myocardial tissue beyond the vasculature, consistent with UHPLC-MS/MS findings. These results demonstrate that BPM31510 targets bioactive CoQ10 to metabolically active tissues, overcoming limitations of oral supplementation, and may provide therapeutic benefit for primary and secondary CoQ10 deficiencies and other mitochondrial or metabolic disorders marked by impaired redox balance and energy homeostasis.

Abstract Defective energy metabolism has been established as a hallmark of cancer; however, the specific genetic basis underlying this relationship across cancers remains unclear. Ubiquinone (CoQ10) plays an essential role in regulating efficient generation of mitochondrial ATP and reactive oxygen species levels. Multi-omics assessment of the CoQ10 biosynthesis pathway genes in The Cancer Genome Atlas Program (TCGA) revealed Kidney Clear Cell Carcinoma (KIRC) and Kidney Papillary renal cell carcinoma (KIRP) as cancers that demonstrated a significant relationship between poor prognosis and low expression or copy number deletions in the CoQ10 biosynthesis genes. However, the link between deletions and low expression in CoQ10 biosynthesis genes and poor outcomes remains unknown. Towards this aim, we defined the CoQ10 interactome as a set of 37 protein encoding genes that bind with CoQ10, along with enzymes involved in downstream pathways impacted by CoQ10 homeostasis, based on literature review. We then investigated this CoQ10 interactome for their association with outcomes for KIRC and KIRP patients in TCGA datasets. First, patients were grouped into low/high expression groups based on median gene expression levels for the indication. We then investigated the association of outcome measures Overall Survival (OS) and Progression Free Interval (PFI) with expression groups in KIRC (n=530) and KIRP (n=288) patients. Our results found that low gene expression in 21 of 37 CoQ10 interactome genes in KIRC, and 3 of 37 CoQ10 interactome genes in KIRP were associated with significantly worse OS and PFI. Next, we analyzed copy number deletions and their association with patient outcomes. Patients were grouped as having a deletion in the gene or not. In line with the prior analysis, we observed that deletions in 9 of 37 CoQ10 interactome genes, and 12 of 37 CoQ10 interactome genes were associated with significantly worse OS and PFI in KIRC and KIPR, respectively. Notably, we observed that deletions in ETHDH (KIRC OS HR = 1.95, q-value = 0.0045, n deletion = 75; KIRP OS HR = 5.42, q-value = 0.00008, n deletion = 28) and PRODH (KIRC OS HR = 2.06, q-value = 0.0144, n deletion = 41; KIRP OS HR = 2.71, q-value = 0.01866, n deletion = 60) were associated with significantly poorer OS and PFI in both KIRC and KIRP. These results demonstrate that CoQ10 and its interactome are significantly impacted in kidney cancer subtypes and deletions or low expression in these key genes are associated with poorer survival outcomes for patients. This data indicates potential for therapeutic intervention with BPM31510, a nanoparticle formulation of oxidized CoQ10, which is currently in Phase 2 clinical trials for oncology indications. Citation Format: Gregory M. Miller, Nischal Mahaveer Chaud, Catarina M. Quinzi, Brian Berman, Vivek K. Vishnudas, Vijay Modur, Vlatcheslav Akmaev, Niven R. Narain, Stephane Gesta, Michael A. Kiebish. Integrated multiomics analysis identifies defective CoQ10 interactome in human kidney cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1274.

BPM31510IV dosing cohorts for monotherapy (Arm 1) and combination therapy (Arm 2).

PK parameters from patient serum at cycle 1 week 1.

Best response to BPM31510IV patients who had at least one tumor imaging assessment at or following Cycle 2.

Results from exploratory studies. A, Representative 18FDG PET/CT scans. A 53-year-old male with gastric adenocarcinoma with liver and lymph node metastases who received BPM31510IV monotherapy at 66 mg/kg. At the end of two cycles of BPM31510IV, there was a 40% decrease in SUV measures, complete resolution of activity in cervical and lymph node metastases, and decreased activity in the liver (yellow arrows). B, Waterfall plot showing best change in sum SUVmax for all patients with PET/CT results. For patients who crossed over from arm 1 to arm 2, PET/CT scan data after crossover were omitted from the analysis. C, Metabolomics analysis identifies metabolic activity involving fatty acylcarnitines associated with BPM31510IV treatment: enrichment for chemical subclasses among plasma metabolites shows a positive association with plasma CoQ10 levels. Chemical subclasses (y-axis) are shown in terms of their significance (x-axis and dot color) and enrichment ratio relative to the reference metabolome (dot size).

Waterfall plots showing best response to BPM31510IV patients who had at least one tumor imaging assessment at or following Cycle 2, by cohort. A., Arm 1. B, Arm 2.

Metabolites detected in plasma or urine that correlate with systemic protein changes. Further information on the column names is provided in the Patients and Methods and the legend for Table S13.

Treatment-emergent adverse events (TEAEs; all grades) that occurred in ≥10% of patients in any group treated with BPM31510IV.

Kaplan–Meier curves showing median progression-free survival for patients in each dosing cohort and treatment arm.

Demographic information and baseline characteristics for patients enrolled in this phase Ia/Ib study of BPM31510IV.

Purpose: BPM31510IV, a highly bioavailable intravenously administered coenzyme Q10 (CoQ10) formulation, was evaluated in a phase Ia/Ib study as monotherapy and in combination with chemotherapy in patients with advanced solid tumors. Patients and Methods: Using a 3 + 3 design, patients received twice-weekly intravenous infusions of BPM31510IV monotherapy (arm 1) or combined with gemcitabine, 5-fluorouracil/leucovorin, or docetaxel (arm 2); crossover between arms was permitted. Tumor response was assessed by RECIST1.1. Pharmacokinetic and multiomics pharmacodynamic (PD) analyses were performed on plasma and core biopsy samples. Results: A total of 97 patients were enrolled, 33 in arm 1 and 71 in arm 2 (seven patients crossed from arm 1 to arm 2). The MTD was 171 mg/kg for BPM31510IV monotherapy or with 5-fluorouracil/leucovorin and 110 mg/kg with gemcitabine or docetaxel. Four dose-limiting toxicities occurred (two in monotherapy; two in combination with chemotherapy). Most adverse events were coagulation-related, occurring in 96% of patients (grade ≥3 in 4%). Pharmacokinetics showed dose-proportional increases in CoQ10 levels to supraphysiologic concentrations (>200×). In arm 1, there was one (3%) partial response (PR), with stable disease (SD) reported in eight (24%) patients. In arm 2, there was one (1%) PR, with SD reported in 25 (35%) patients. Fluorodeoxyglucose-PET imaging and PD data suggest a change in tumor metabolism from glycolysis to oxidative phosphorylation. Conclusions: BPM31510IV as monotherapy and in combination with chemotherapy was safe, with preliminary evidence of antitumor activity. High plasma CoQ10 levels were achieved, inducing PD responses consistent with mitochondrial metabolic changes. These findings support continued clinical development of BPM31510IV. Significance: BPM31510IV is a lipid nanodispersion of oxidized CoQ10 that alters the Warburg effect and displays anticancer activity. BPM31510IV seems to synergize with chemotherapy to induce cancer cell apoptosis, likely through mitochondrial priming. An initial phase I monotherapy study demonstrated that BPM31510IV is well tolerated in patients with advanced solid tumors. Based on these observations, the safety and preliminary antitumor activity of BPM31510IV were further explored in a phase Ia/Ib study in combination with chemotherapy. Results indicated that BPM31510IV monotherapy and BPM31510IV combined with chemotherapy are well tolerated, demonstrating preliminary evidence of antitumor activity and inducing physiologic and molecular changes consistent with altered mitochondrial metabolism. The most common adverse events were changes in coagulation parameters. Overall, this study provides valuable MTD and surrogate efficacy data that support the continued clinical development of BPM31510IV.

Treatment-emergent adverse events (TEAEs; all grades) that occurred in ≥10% of patients in any group treated with BPM31510IV in Arms 1 and 2 stratified by cohort.

All treatment-emergent adverse events (TEAEs) resulting in discontinuation of study drug attributed by the Investigator to the study treatment.

GBM is characterized by altered metabolic activity driven by several factors including lower CoQ10 levels resulting in reduced oxidative phosphorylation and higher glycolytic dependence compared to normal neural tissue. BPM31510 is a novel drug-lipid conjugate nanodispersion that achieves high levels of oxidized CoQ10 following IV infusion that in preclinical studies shows metabolic rewiring in GBM cells and generation of reactive oxygen species (ROS) resulting in selective cancer cell apoptosis. Treatment with BPM31510 is associated with tumor response and long-term survival of C6 glioma rat model. In Phase 1 GBM trial (NCT0302060), BPM31510 reduced plasma circulating markers associated with glioma progression, including KITLG (the ligand for the receptor-type protein tyrosine kinase KIT), the oncogenic driver SRC (SRC proto-oncogene, non-receptor tyrosine kinase), and carboxypeptidase Q. Given that the expression of KITLG and SRC is known to be upregulated by cancer cells under hypoxic conditions, the observed reduction in these markers suggests that BPM31510 may mitigate tumor hypoxia in patients as well. The ongoing Phase 2 trial in newly diagnosed patients with glioblastoma investigates the hypothesis of whether reprogramming of mitochondrial metabolism with BPM31510 results in improved efficacy of TMZ and radiotherapy in the frontline adjuvant setting. (BPM31510IV-11; NCT04752813) is a single-arm, open-label, phase 2 study of BPM 31510 + Vitamin K1 with standard chemoradiation and TMZ in newly diagnosed GBM patients. The primary endpoint is progression free survival at 6 months (PFS6) while the secondary endpoints are overall survival, PFS12 and safety. Exploratory endpoints include effects of BPM31510 on metabolism and change in markers associated with glioma progression. Patients with recent hemorrhage, coagulopathy or requiring anticoagulants are excluded. Intravenous BPM31510 is initiated 2-4 weeks after biopsy or tumor resection. After two weeks of BPM31510 treatment, standard chemoradiation and TMZ is started in combination with weekly BPM31510 treatment. After 8 weeks, BPM31510 treatment ends with the end of standard RT schedule. Subjects continue to receive maintenance TMZ treatment for up to 12 cycles as per standard of care. Approximately 50 patients will be enrolled. A 90% power in rejecting the null hypothesis of PFS6 of ≤ 30%. The study is currently open at 8 US sites and has enrolled 20 patients. Brian Stocksdale, Rebecca Brown, Kevin Elmore, Chirag Patel, Adam Cohen, Rupa Juthani, Brian Vaillant, Alexander Spira, Jedrzej Wykretowicz, Bing Nie, Michael A. Kiebish, Stephane Gesta, Niven R. Narain, Vijay Modur, Seema Nagpal. A phase 2 study of BPM31510 (a lipid nanodispersion of oxidized CoQ10) with vitamin K in combination with standard of care (SOC) RT and TMZ in glioblastoma multiforme (GBM) patients without prior therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT242.

Cancer therapy is transforming from traditional chemotherapeutic agents (CTAs) to innovative immunotherapies. Despite this shift, chemotherapy remains clinically stable, as CTAs are thought to convert the tumor microenvironment (TME) from immunosuppressive to immune-active by inducing immunogenic cell death (ICD) in tumor cells which leads to stimulation of immune cells. This ICD induction is thought to be crucial for enhancing the efficacy of immunotherapies. Thus, using CTAs as ICD agents—alone or in combination with immunotherapies—may offer significant anti-cancer benefits and new treatment avenues. This study investigates the potential of BRG399, a novel microtubule-binding agent, as an immunogenic cell death (ICD) inducer utilizing preclinical in vitro and in vivo models. Treatment of cancer cell lines with BRG399 showed a dose-dependent increase in surface calreticulin and secreted HSP70, measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The enhancement of both ICD markers was comparable to that observed with established ICD agents. To explore the potential of BRG399 to exert influence on immune-regulated anti-tumor effects, in vivo studies in immune-competent syngeneic models were conducted with measurable endpoints of tumor growth inhibition and TME composition by flow cytometry and TIMS TOF spatial omics. BRG399 displayed anti-tumor activity while largely preserving tumor-associated immune cells and notably modifying the immune cell landscape within the tumor. Our findings suggest that BRG399 acts as an ICD agent, effectively modulating both tumor and immune cells within the TME and highlighting its potential for future combination therapies with immunotherapeutics. Further in vivo studies are currently being conducted to comprehensively elucidate the immune-mediated effects of BRG399 aiming to clarify its role in enhancing anti-tumor responses ultimately contributing to the development of more effective cancer therapies. Kaila M. Bennett, Jacob P. Matson, Sylwia Stopka, Juan J. Aristizabal-Henao, Archna Ravi, Andressa L. Mota, Dinesh Chimmanamada, Vivek K. Vishnudas, Stephane Gesta, Maria-D Nastke. Exploring BRG399, a novel microtubule-binding agent, as an inducer of immunogenic cell death in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6161.

Changes in specific plasmalogen molecular species based on regression analysis. Further information on the column names is provided in the Patients and Methods and the legend for Table S13.