P5091 / Progenra - LARVOL DELTA

Dual Covalent Targeting of STING Cysteines 292/309 Disrupts Functional Oligomerization and Enables Potent Antagonist Development. (PubMed, Adv Sci (Weinh)) - "Through covalent warhead repurposing, we identified P005091, previously known as a USP7 inhibitor, as a STING antagonist that operates via a non-classical nucleophilic displacement mechanism...Structure-guided optimization yielded the advanced compounds NTP14 and NTP16, which exhibit markedly enhanced cellular potency and robust efficacy in ameliorating type I interferon-driven pathology in multiple preclinical models, including DSS-induced colitis. Our work establishes dual covalent CTD targeting as a transformative strategy for STING antagonist development and opens a new therapeutic avenue for quenching STING-driven inflammation at its source."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • STING • USP7

USP7 inhibitor synergistically enhanced the anticancer effect of the KRAS G12C inhibitor by effectively countering feedback signaling pathways (AACR 2026) - "KRAS G12C-mutant NSCLC cells and in vivo xenograft models were treated with KRAS G12C specific inhibitor (GDC-6036) and USP7 inhibitor (P5091), either alone or in combination, to evaluate the combinatorial antitumor effects. The combination of KRAS G12C and USP7 inhibitors significantly enhances the anticancer effect by suppressing KRAS feedback signaling, modulating multiple oncogenic and metabolic pathways, and promoting apoptosis in cancer cells, representing a promising novel approach to achieve durable therapeutic benefits of KRAS blockade in NSCLC, warranting further investigation."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • KRAS • USP7

USP7 protects histone H1.2 from proteasome-mediated degradation to facilitate DNA repair and pancreatic neuroendocrine neoplasms progression. (PubMed, Sci China Life Sci) - "In conclusion, USP7 was a key regulator of DNA repair in pNENs. The combination of cisplatin and P005091 therefore holds promise as a therapeutic strategy for pNENs."

Journal • Endocrine Cancer • Neuroendocrine Carcinoma • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • USP7

Spotlights on ubiquitin-specific proteases in lung cancer: from multifaceted pathophysiological mechanisms to potential therapeutic targets. (PubMed, PeerJ) - "Recent studies indicate that multiple Ubiquitin-Specific Proteases (USP) family members play pivotal roles in lung cancer: Ubiquitin-Specific Peptidase 7 (USP7) promotes proliferation and osimertinib resistance in non-small cell lung cancer by stabilising proteins such as ERβ, c-Abl, and KRAS; Ubiquitin-Specific Peptidase 9, X-linked (USP9X) mediates radiotherapy resistance by regulating KDM4C and REV1; USP10 influences cellular metabolism and chemotherapy sensitivity via PTEN/AKT/mTOR and HDAC6 pathways; Ubiquitin-Specific Peptidase 14 (USP14) enhances tumour migration by regulating β-catenin and Acf7 stability; Ubiquitin-Specific Peptidase 22 (USP22) amplifies tumour stem cell properties and suppresses ferroptosis via EGFR and BMI1 signalling; Ubiquitin-Specific Peptidase 35 (USP35) and Ubiquitin-Specific Peptidase 38 (USP38) respectively modulate apoptosis resistance and proliferation through BIRC3 and KLF5; while Ubiquitin-Specific Peptidase 39 (USP39)..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ABL1 • BIRC3 • BMI1 • CTNNB1 • KLF5 • KRAS • PTEN • TGFB1 • USP1 • USP14 • USP22 • USP7 • USP9X

USP7 inhibitor P5091 enhances the antitumor efficacy of vemurafenib in BRAFV600E-mutant thyroid cancer via ferroptosis. (PubMed, Biochem Pharmacol) - "Given USP7's role in oxidative stress and ferroptosis, we examined its involvement and found that P5091 induced ferroptosis via reactive oxygen species (ROS) elevation, glutathione peroxidase 4 (GPX4) downregulation, and elevated lipid peroxidation. These findings demonstrate that USP7 inhibition by P5091 enhances PLX4032 efficacy by promoting tumor suppression and ferroptosis in BRAFV600E-mutant thyroid cancer, offering a promising strategy to overcome resistance."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • GPX4 • ITGB3 • USP7

Empagliflozin Attenuates Diabetic Cardiomyopathy via Inhibiting Cardiomyocyte Ferroptosis Through the USP7/NRF2 Signaling Pathway. (PubMed, Antioxid Redox Signal) - "The ferroptosis inducer erastin abolished the protective effects of Empa...Administration of the USP7 inhibitor P5091 abolished the effects of Empa, whereas the use of adeno-associated virus serotype 9 (AAV9)-NRF2 reversed the effects of P5091...00, 000-000. 2022-SYDWLL-000213."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Targeted Protein Degradation • GPX4 • USP7

Targeting USP47 enhances immunotherapy in hepatocellular carcinoma by destabilizing PD-L1. (PubMed, Int Immunopharmacol) - "USP47 is essential for modulating proliferation, migration, invasion, and immune evasion of HCC cells. Inhibiting USP47 in combination with PD-1 blockade can enhance the suppression of HCC growth, potentially holding clinical importance. This investigation elucidates the role of USP47 in PD-L1 stability via deubiquitination, offering a new prognostic indicator and potential target for treating HCC."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PD-L1 • USP47

USP7 - A novel target for controlling periodontal inflammation through modulation of macrophage polarization. (PubMed, Immunol Lett) - "Inhibition of USP7 with P5091 resulted in the decreased expression of M1 polarization markers and phosphorylation of P65, but the increased expression of M2 polarization markers and phosphorylation of STAT6. In conclusion, USP7 is involved in regulating macrophage polarization in periodontitis and its inhibitor P5091 may contribute to the prevention of periodontitis."

Journal • Dental Disorders • Inflammation • Periodontitis • Targeted Protein Degradation • IFNG • IL4 • USP7

Redox-Induced Stabilization of AMBRA1 by USP7 Promotes Intestinal Oxidative Stress and Colitis Through Antagonizing DUB3-Mediated NRF2 Deubiquitination. (PubMed, Adv Sci (Weinh)) - "Notably, the USP7 inhibitor, P5091, inhibits oxidative stress and colitis in vivo. Elevated AMBRA1 expression in inflamed colon tissues from ulcerative colitis patients is negatively correlated with decreased NRF2 protein levels. Overall, this study identifies AMBRA1 as a pro-oxidative factor in IECs and provides a redox-modulating therapeutic strategy for targeting USP7/AMBRA1 in IBD."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Targeted Protein Degradation • Ulcerative Colitis • AMBRA1 • BECN1 • USP7

Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth. (PubMed, J Transl Med) - "This study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • MYC • USP7

USP7 Inhibition Promotes Early Osseointegration in Senile Osteoporotic Mice. (PubMed, J Dent Res) - "The selective inhibitor of USP7, P5091, has also been found to promote bone repair and homeostasis in osteoporotic conditions...This has implications for understanding the cellular interactions and signaling mechanisms in the peri-implant bone microenvironment under osteoporotic conditions. It may also provide clinical significance in developing new therapies to enhance osseointegration quality and shorten the edentulous period in elderly osteoporotic patients."

Journal • Preclinical • Dyslipidemia • Inflammation • Osteoporosis • Rheumatology • Targeted Protein Degradation • LRP1 • USP7

USP7 regulates growth and maintains the stemness of p53-mutant colorectal cancer cells via stabilizing of mutant p53. (PubMed, Front Oncol) - "Furthermore, USP7 inhibitor P5091 also diminished CCSCs self-renewal and reduced mutant p53 levels. Taken together, our findings demonstrated that USP7 involved in the modulation of CCSCs stemness, as well as a critical target for clinical treatment of cancers with different p53 mutations."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TP53 • USP7

PRMT1 promotes Warburg effect by regulating the PKM2/PKM1 ratio in non-small cell lung cancer. (PubMed, Cell Death Dis) - "Melatonin, a hormone that inhibits glucose intake, markedly suppressed cell proliferation of p53 wild-type NSCLC, while a combination of melatonin and the USP7 inhibitor P5091 enhanced the anticancer activity in p53-deficient NSCLC. Our collective findings support a role of PRMT1 in the regulation of Warburg effect in NSCLC. Moreover, combination treatment with melatonin and the USP7 inhibitor showed good efficacy, providing a rationale for the development of PRMT1-based therapy to improve p53-deficient NSCLC outcomes."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PKM • PRMT1 • PTBP1 • USP7

FOXO1-MEDIATED CELL CYCLE ARREST AND APOPTOSIS IS INHIBITED BY USP7 DOWNSTREAM OF BCR LIGATION IN CLL CELLS. (EHA 2024) - " Treatment of MEC1 and CLL patient samples with DUB inhibitors PR-619, P5091 and HBX19818 alone reducedAKTS437 and FOXO1T24 phosphorylation, indicating DUBs play a role in inhibiting FOXO1 activity. These studies indicate that selective DUBs, in particular USP7, play a role in BCR-mediated signalling to aid inthe promotion of CLL cell survival and chemo-resistance through FOXO1 inhibition, and inhibiting USP7enhances FOXO1 activity promoting cell cycle arrest and apoptosis."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • FOXO1 • PTEN • USP7

Targeting USP7 to induce ubiquitination degradation of oncogenic ATAD2 and effects on cholangiocarcinoma growth. (ASCO 2024) - "This study uncovers the role of USP7-ATAD2 axis in regulating tumor growth, and targeting USP7 may provide a novel therapeutic strategy for CCA."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ATAD2 • USP7

Targeting senescent HDF with the USP7 inhibitor P5091 to enhance DFU wound healing through the p53 pathway. (PubMed, Biochem Biophys Res Commun) - "This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells. This provides a new senolytics target and experimental basis for promoting DFU wound healing."

Journal • Diabetes • Targeted Protein Degradation • CDKN1A • USP7

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation. (PubMed, Acta Pharmacol Sin) - "We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect...In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD8 • FGL1 • PRDM1 • USP7

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

Examination of cancer cell survival using AI confluence analysis | Poster Board #2430 (ACS-Sp 2024) - "Clonogenic cell survival curves for cell line MiaPaca-2 indicated that radiation and radiation used in conjunction with 10µM P5091 radiosensitizer had a negative impact on cell growth and survival after 14 days...The data generated by AI confluence analysis was found to be similar to that of clonogenics and could be used to make the same inferences regarding cell growth. AI confluence analysis was found to be a useful, efficient alternative to a traditional clonogenic assay."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Deubiquitylase USP7 plays a crucial role in the lineage differentiation of preimplantation blastocysts. (PubMed, Biol Reprod) - "Our results showed that RNAi-mediated silencing of USP7 in mouse embryos or treatment with P5091, a small molecule inhibitor of USP7, significantly reduced blastocyst rate and blastocyst quality, and decreased total and TE cell numbers per blastocyst, as well as destroying normal lineage differentiation...Notably, USP7 may regulate the transition from the morula to blastocyst by stabilizing the target protein YAP through the ubiquitin-proteasome pathway. In conclusion, our results suggest that USP7 may play a crucial role in preimplantation embryonic development by regulating lineage differentiation and key epigenetic modifications."

Journal • Targeted Protein Degradation • CDX2 • NANOG • POU5F1 • SOX2 • USP7

B cell receptor-mediated signals modulate rapid FOXO1 upregulation in chronic lymphocytic leukaemia: a role for deubiquitinate proteins? (IWCLL 2023) - "Treatment of the CLL cell line MEC1 and primary CLL patient samples with DUB inhibitors including PR-619 (pan-DUBi), P5091 (USP7i) and HBX19818 (USP7i) alone reduces the phosphorylation of AKTS437 and FOXO1T24, indicating that DUBs play a role in inhibiting FOXO1 activity. Additionally, FOXO1 activity studies demonstrated significant activation of FOXO1 upon ibrutinib treatment, which was further enhanced in the USP7 KD and combination with USP7i. These studies suggest that selective DUBs play a role in BCR-mediated signalling to aid in the promotion of CLL cell survival and chemo-resistance through FOXO1 inhibition, and targeting these DUBs enhance FOXO1 activity leading to cell cycle arrest and apoptosis."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BAK1 • BCL2 • BCL2L11 • CCND2 • CCNG2 • CDKN1A • FOXO1 • PTEN • USP14 • USP7 • USP8 • USP9X

USP7 promotes the osteoclast differentiation of CD14+ human peripheral blood monocytes in osteoporosis via HMGB1 deubiquitination. (PubMed, J Orthop Translat) - "In vivo, P5091 effectively attenuates bone loss in OVX mice. We demonstrate that USP7 promotes the differentiation of CD14+ PBMCs into osteoclasts via HMGB1 deubiquitination and that inhibition of USP7 effectively attenuates bone loss in osteoporosis in vivo.The translational potential of this article:The study reveals novel insights into the role of USP7 in the progression of osteoporosis and provides a new therapeutic target for the treatment of osteoporosis."

Journal • Osteoporosis • Rheumatology • Targeted Protein Degradation • CD14 • HMGB1 • USP7

CRIP1 INDUCES PIS RESISTANCE BY FORMING A COMPLEX WITH USP7 /PA200 AND ENHANCING PROTEASOME ACTIVITY AND AUTOPHAGY IN MULTIPLE MYELOMA (EHA 2023) - "CRIP1 overexpress and doxycycline-inducible CRIP1-shRNA cell lines were constructed to explore the role of CRIP1 in MM...Caspase-like (C-L), chymotrypsin-like (CT-L), and trypsin-like (T-L) peptidase activity of the proteasome in MM cells were significantly reduced with CRIP1 knockdown...The protein level of CRIP1 decreased and the ubiquitination CRIP1 increased after P5091 treatment or with USP7 knockdown... CRIP1 plays a critical role in MM progression and PIs resistance by formation of CRIP1/USP7/PA200 complex.High level of CRIP1 is a biomarker for high-risk MM patients. CRIP1 is a potential target for MM therapy, can simultaneously inhibit proteasome activity and autophagy. Multiple myeloma, Protein-protein interaction, Drug resistance, Proteasome inhibitor"

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRIP1 • USP7

Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors. (PubMed, Cell Rep) - "Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma."

Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRAF • NRAS • RRM2 • USP7

Targeting USP7/RRM2 axis drives senescence and sensitizes melanoma cells to epigenetic drugs (EACR 2022) - "We also establish a central role of USP7/RRM2 axis in melanoma maintenance. Importantly, our work sheds light on alternative therapeutic option to melanoma patients increasing the efficacy of P5091; targeting the residual, senescent cells with domatinostat."

Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • RRM2