VLX1570 / Vivolux - LARVOL DELTA

Overcoming Cisplatin Resistance in Urothelial Carcinoma: The Role of Protein Deubiquitinase Inhibitors in Targeting Proliferating Cell Nuclear Antigen - A Combined In Vitro and In Vivo Approach (AUA 2024) - "Our study revealed that deubiquitination activities have a strong relationship with chemoresistance in metastatic UC, which highlights a promising strategy to tackle chemoresistance. Furthermore, VLX1570 enhances the cytotoxic and apoptosis-inducing effects of cisplatin, an effect that aligns with the downregulation of proliferating cell nuclear antigen (PCNA). Such insights set the stage for the development of innovative therapies that combine chemotherapy agents with VLX1570 to effectively address UC chemoresistance."

Preclinical • Bladder Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Urothelial Cancer • PCNA • UCHL5 • USP14

An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell carcinoma (AACR 2024) - "Moreover, the combination treatment suppressed tumor growth in vivo more effectively than either VLX1570 or temsirolimus alone. These findings suggest that UCHL5/USP14 plays a role in RCC progression and prognosis, making it a promising therapeutic target for overcoming drug resistance in this cancer."

IO biomarker • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PCNA • UCHL5 • USP14

Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly. (PubMed, ACS Chem Biol) - "Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular cross-linking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, further support the continued development of electrophilic compounds that target reactive cysteine residues on NLRP3 to regulate its activation and activity."

Journal • Inflammation • IL18 • IL1B • NLRP3

A carboxy-terminal ubiquitylation site regulates androgen receptor activity. (PubMed, Commun Biol) - "An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases...Mutagenesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications at K313 differentially regulate AR activity. Together these studies expand the spectrum of AR posttranslational modifications, and indicate that the K911 site may regulate AR turnover on chromatin."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Comparison of Data from Fresh and Frozen AML Samples for Functional Drug Testing (ASH 2022) - "Samples that had been frozen were more sensitive to drugs such as kinase inhibitors (amcasertib, dinaciclib), as well as apoptotic modulators (S-63845), and proteasome inhibitors (VLX1570). Additionally, fresh samples were more sensitive to paclitaxel than frozen ones across the paired samples.The cell composition of paired samples was also affected by cryopreservation, with a reduction in the frequency of cells expressing c-KIT (CD117) and a reduction of cells with high granularity (side scatter)...However, careful consideration should be given to the specific drugs and cell populations of interest before deciding on sample handling methodology. This may be of particular importance when investigating specific drugs and phenotypes affecting cell proliferation and maturation stage, as sample handling may induce systematic differences and confound interpretation."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • ITGAM • KIT • NCAM1

Histone deacetylase inhibitor, panobinostat, exerts anti-proliferative effect with partial normalization from aberrant epigenetic states on granulosa cell tumor cell lines. (PubMed, PLoS One) - "Combined treatment of PS with a deubiquitinase inhibitor, VLX1570 enhanced the expression of p21, cleaved PARP, cleaved caspase-9, heme oxygenase-1, and the acetylation of histone H4 and α-tubulin, leading to an additive anti-proliferative effect on KGN and COV434. Exposure of KGN and COV434 cells to PS increased the expression of E-cadherin, one of the principal regulators associated with adherens junction in quantitative RT-PCR and immunoblotting analysis. In the present study, we indicate a basis of a novel therapeutic availability of a HDAC inhibitor for the treatment of GCTs and further investigations will be warranted."

Epigenetic controller • Journal • Preclinical • Oncology • Targeted Protein Degradation • CASP9 • CDH1 • CDKN1A • HMOX1

VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway. (PubMed, J Cell Mol Med) - "Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti-lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ATF6 • CCNB1 • CDK1 • ERN1

Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System. (PubMed, Biomolecules) - "To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines. (PubMed, Cancer Sci) - "VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitine proteasome system, the expression of heme oxygenase-1 and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP-1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti-leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • ATF4 • HMOX1

Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma. (PubMed, Cells) - "Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology

Inhibition of the ubiquitin proteasome system in cancer by b-AP15 (AACR 2018) - "...The 20S proteasome inhibitors bortezomib, carfilzomib and ixazomib have achieved FDA and EMA approval for clinical use for multiple myeloma and other cancers...We have previously reported that the small molecules b-AP15/VLX1570 inhibit proteasome deubiquitinase (DUB) activity, primarily inhibiting USP14 (DArcy et al., Nat Med 2011)...Quiescent cancer cells were found to survive treatment, and when able to re-enter the cell cycle able to form drug-sensitive progeny. Overall these findings indicate that proteasome DUB activity is promising target for cancer therapeutics."

Multiple Myeloma

Dienone Compounds: Targets and Pharmacological Responses. (PubMed, J Med Chem) - "Here we review in vitro and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613...Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models."

Journal • Oncology • Targeted Protein Degradation • TP53

Re-evaluating the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: a paradigmatic example of unspecific protein crosslinking with Michael acceptor motif-containing drugs. (PubMed, J Med Chem) - "Activity-based proteome profiling identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, and further analysis demonstrated that high molecular weight complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce non-specific protein aggregation, providing a molecular explanation for general cellular toxicity."

Journal • CNS Disorders • Targeted Protein Degradation

Waldenstrom Macroglobulinemia Cells Modulate Mitochondrial Bioenergetics and Induce a Respiratory Hyper-Drive State upon Acquisition of Ibrutinib-Resistance (ASH 2016) - "While our focus was mitochondrial bioenergetics and its therapeutic relevance in drug-resistant WM, unexpectedly we observed for the first time, evidence that VLX1570 induces changes in mitochondrial bioenergetics as early as 2hrs leading to increased mitochondrial membrane permeability and cell apoptosis in 6-12hrs. Comparable observations were made with bortezomib (targeting 20S). This is the first report identifying the role of mitochondrial hyper-drive in WM cells with resistance to ibrutinib. Of note, enhanced mitochondrial bioenergetics in the IR state increased sensitivity to proteasome inhibition and this was independent of the site of disruption in the proteasome pathway. Although, WES findings alone were not sufficient in explaining mitochondrial overdrive noted in our system, ongoing analysis of various mitochondrial functions (Fig."

Biosimilar • Chronic Lymphocytic Leukemia • Hematological Malignancies • Indolent Lymphoma • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570. (PubMed, Int J Mol Sci) - "Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14 (AACR 2017) - "...An optimised lead of b-AP15 (VLX1570) has been approved by the FDA for clinical studies and is currently in clinical trials for relapsed multiple myeloma...We also provide additional understanding of drug-target interactions using a series of compounds identified by screening. Our findings demonstrate promising antiproliferative activities of USP14 inhibitors in vitro and in vivo."

Biosimilar • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Sarcoma

Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15. (PubMed, PLoS One) - "The proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use."

Journal • Preclinical

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma. (PubMed, Invest New Drugs) - "Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit."

Clinical • Journal • P1 data