P22077 / Progenra - LARVOL DELTA

A ubiquitin specific protease (USP) network regulates wnt/β-catenin activity in myeloid leukemia cells (ASH 2025) - "Consistent with this lentiviral mediated suppression of individual USPs via shRNA, did not impact β-catenin stability or nuclear translocation but pan inhibitors of DUB activity (DUBi) including WP1130, P22077, and PR619 all significantly reduced Wnt signalling output (TCF/LEF activity) suggesting alternative mechanisms of Wnt signalling regulation. Specifically, further investigation into USP48 found it to be a predominantly nuclear localised USP and although shRNA mediated depletion did not impact overall β-catenin level, we observed accelerated nuclear β-catenin exit dynamics upon withdrawal of the Wnt agonist CHIR99021 in myeloid cell lines, suggesting a role for USPs in the nuclear retention/stability of β-catenin. These findings highlight a novel and complex role of USPs in regulating Wnt signalling activity in leukaemia cells and may provide new therapeutic strategies for limiting aberrant nuclear β-catenin via USP48 targeting in myeloid leukaemia."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • USP5

FLT3-ITD Signaling Continuously Degrades p53 By the Ubiquitin-Proteosome Pathway Explaining Chemo-Resistance (ASH 2024) - "(ii) The small molecule P22077 is a specific modifier of the catalytic site in USP7 but not other deubiquitinases (Pozhidaeva...Bortezomib to inhibit the 26S proteasome increased p53 and activated apoptosis specifically in FLT3-ITD but not FLT3-WT AML cells, results reproduced with MG-132 that inhibits the 20S proteosome...Cell Rpts Med 2023; 4(11) : 101286). Presently, midostaurin to inhibit FLT3-ITD signaling is ingested on days after infusional chemotherapy - the mechanisms shown here suggest ingestion simultaneous or immediately-after chemotherapy, so that p53 is more available to respond to chemotherapy stress and activate apoptosis – timings again supported by in vitro studies by others"

Acute Myelogenous Leukemia • Targeted Protein Degradation • CEBPA • FLT3 • GLI2 • USP7

Deubiquitinating Enzymes in Osteoarthritis: From Mechanisms to Therapeutic. (PubMed, Orthop Rev (Pavia)) - "Pre-clinically, small-molecule USP7 inhibitors (P22077), USP14 inhibitors (IU1) and genetic silencing of USP15 or USP49 have all been shown to reduce cartilage loss and inflammatory pain in mouse OA models. Collectively, these findings establish DUBs as druggable nodes in OA and underscore the need for selective inhibitors that can safely modulate ubiquitin-dependent protein turnover in human joints.However, DUB research remains nascent, requiring further validation of their clinical efficacy and safety. This review elucidates DUB-mediated mechanisms in OA and discusses challenges in developing selective DUB inhibitors for future therapies."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • Targeted Protein Degradation • NFKBIA • NLRP3 • NOX4 • PTEN • TGFB1 • TRAF6 • USP13 • USP14 • USP5 • USP7

FUS-stabilized USP7 facilitates the bevacizumab resistance of ovarian cancer through deubiquitinating PTK2. (PubMed, J Gynecol Oncol) - "FUS-stabilized USP7 enhanced the bevacizumab resistance of OC by deubiquitinating PTK2, providing a new idea for overcoming bevacizumab resistance in OC."

Journal • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • Targeted Protein Degradation • FUS • PTK2 • TYK2 • USP7

Multifunctional regulation and treatment of ubiquitin specific protease 10. (PubMed, Biochem Pharmacol) - "USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential."

Journal • Review • Brain Cancer • Breast Cancer • Cardiovascular • CNS Disorders • Glioblastoma • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Novel Coronavirus Disease • Oncology • Pancreatic Cancer • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • AMPK • AXIN1 • CCND1 • CTNNB1 • G3BP1 • HDAC7 • PTEN • RUNX1 • USP13 • YAP1

Targeting oncogenic FLT3-ITD by USP10 inhibitors for the treatment of FLT3-ITD AML (AACR 2025) - "Gilteritinib was recently approved for relapsed/refractory (R/R) FLT3-mutated AML patients...Additionally, the USP7 inhibitor P22077 has demonstrated antileukemic activity and also targets USP10 in AML cells...Furthermore, GL-320 induces apoptosis in FLT3-ITD AML cells through inhibition of USP10 and subsequent downregulation of FLT3-ITD and PARP1 independent of caspase activation, and pharmacological inhibition of these two proteins induced apoptosis in a cooperative manner. Our results demonstrate that GL-320 is a non-covalent USP10 inhibitor that shows potent in vitro antileukemic activity against FLT3-ITD AML."

Late-breaking abstract • Acute Myelogenous Leukemia • Oncology • FLT3 • PARP1 • USP1 • USP7

Involvement of USP7 in aggravating Kawasaki disease by promoting TGFβ2 signaling mediated endothelial-mesenchymal transition and coronary artery remodeling. (PubMed, Int Immunopharmacol) - "Importantly, intraperitoneal injection of USP7 inhibitor, P22077 elicited a robust anti-EndoMT and anti-vascular inflammation effect in KD model mice. Therefore, our study uncovered a previously unrecognized function of increased USP7 in KD by augmenting TGFβ2/SMAD2/SMAD3 signaling, thus facilitating the transcription of genes implicated in the EndoMT, cardiac fibrosis, and vascular remodeling. Our finding suggests that USP7 could serve as a potential therapeutic target for the prevention and treatment of coronary artery lesions in KD and related vascular diseases."

Journal • Cardiovascular • Fibrosis • Heart Failure • Immunology • Inflammation • Pediatrics • Targeted Protein Degradation • Vasculitis • CD31 • PECAM1 • SMAD3 • TGFB1 • TGFB2 • USP7

USP7 Promotes TGF-β1 Signaling by De-Ubiquitinating Smad2/Smad3 in Pulmonary Fibrosis. (PubMed, Discov Med) - "This study demonstrates that USP7 promotes TGF-β1 signaling by stabilizing Smad2 and Smad3. The contribution of USP7 to the progression of IPF indicates it may be a viable treatment target."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • COL1A1 • NECTIN1 • SMAD2 • SMAD3 • TGFB1 • USP7

Artesunate attenuates osteoarthritis in mice by promoting MTA1 transcription through a USP7/FoxO1 axis. (PubMed, Toxicol Appl Pharmacol) - "ART alleviates OA in mice by elevating ubiquitin carboxyl-terminal hydrolase 7 (USP7) expression, and USP7 inhibitor (P22077) treatment mitigated the protective effects of ART on chondrocytes...In addition, FoxO1 promoted metastasis-associated protein MTA1 (MTA1) transcription, and downregulation of MTA1 exacerbated chondrocyte injury. Our study identifies that USP7/FoxO1/MTA1 is a key signaling cascade in the treatment of ART on OA."

Journal • Preclinical • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • Targeted Protein Degradation • IL1B • MTA1 • USP7

Inhibitory Effect of P22077 on Airway Inflammation in Rats with COPD and Its Mechanism. (PubMed, Int J Chron Obstruct Pulmon Dis) - " P22077 inhibits expression of NLRP3 pathway-related inflammatory factors and proteins and reduces the airway inflammatory response and inflammatory cell aggregation in COPD rats. The underlying mechanism may be related to the down-regulation of NLRP3 inflammatory vesicle signaling pathway expression."

Journal • Preclinical • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • IL18 • IL1B • NLRP3

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway. (PubMed, Int J Mol Sci) - "However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i."

Journal • Oncology • Targeted Protein Degradation • HSF1 • USP7

Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice. (PubMed, Hypertens Res) - "Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-β/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies."

Journal • Preclinical • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology • Oncology • Targeted Protein Degradation • NLRP3 • NOX4 • SMAD2 • TGFB1 • USP7

Ubiquitination-specific protease 7 enhances stemness of hepatocellular carcinoma by stabilizing basic transcription factor 3. (PubMed, Funct Integr Genomics) - "Gain-of-function and loss-of-function assays were conducted in SK-Hep1 and HepG2 cells transfected with USP7 overexpression/knockdown plasmids and USP7 inhibitor P22077...Overexpression of BTF3 partially rescue the inhibitory effects of USP7 depletion on the malignant phenotypes and stemness properties of SK-Hep1 and HepG2 cells. USP7 can promote the stemness and malignant phenotype of HCC by stabilizing BTF3."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BTF3 • BTN3A2 • TCF3 • USP7

Targeting HAUSP in glioma stem cells inhibits malignant growth and overcomes radioresistance of glioblastoma (SNO 2023) - "Disrupting HAUSP by shRNA or its inhibitor P22077 promoted GSC differentiation, impaired GSC growth, and potently inhibited GBM malignant growth, indicating that HAUSP is required for maintaining the self-renewal and tumorigenic potential of GSCs...Our findings uncover a novel role of HAUSP in maintaining GSC phenotypes and tumorigenic potential, and thus offer a promising druggable target for developing anti-GSC therapeutics to improve GBM treatment. Furthermore, our preclinical data suggest that inhibiting HAUSP alone or in combination with IR may prolong the survival of GBM patients."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • USP7

Prognostic value and immune landscapes of cuproptosis-related lncRNAs in esophageal squamous cell carcinoma. (PubMed, Aging (Albany NY)) - "The above risk score and nomogram can accurately predict prognosis in ESCC patients and provide guidance for chemotherapy and immunotherapy."

IO biomarker • Journal • Tumor mutational burden • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • TMB

FLT3-ITD Degrades CEBPA Via the Ubiquitin-Proteosome Pathway (ASH 2022) - "The FLT3-inhibitors sunitinib and gilteritinib decreased CEBPA S21-P, increased CEBPA total protein measured by Western blot and immunofluorescence, and induced terminal granulocytic differentiation in the FLT3-ITD MOLM13 and MV4-11 AML cells, but not FLT3-WT THP1 or OCI-AML3 cells. Moreover, the proteosome inhibitors bortezomib or MG132 increased S21-P-, ubiquitinated-, and total-CEBPA protein in the FLT3-ITD but not the FLT3-WT AML cells...The small molecule P22077 alters and inhibits USP7 catalytic site conformation: P22077 shifted USP7 deubiquitinase interactions from UHRF1 to CEBPA, decreased UHRF1 and increased total CEBPA (Figure)...In sum, FLT3-ITD signals for CEBPA protein degradation via USP7 and UHRF1, to thereby decouple proliferation from onward lineage-maturation in committed granulo-monocytic progenitors. Overall, this pathway explains FLT3-ITD: (i) origin in committed granulo-monocytic progenitors; (ii) link to suppressed CEBPA-target genes; (iii) mutual..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CEBPA • FLT3 • GLI2 • KIT • UHRF1 • USP7

Administration of USP7 inhibitor P22077 inhibited cardiac hypertrophy and remodeling in Ang II-induced hypertensive mice. (PubMed, Front Pharmacol) - "Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-β/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Immunology • Inflammation • Oncology • Targeted Protein Degradation • NLRP3 • NOX4 • SMAD2 • TGFB1 • USP7