A5001006273- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Histone Deacetylase Inhibitors Research
- Multiple Myeloma Research and Treatments
- Glioma Diagnosis and Treatment
- Peptidase Inhibition and Analysis
- Brain Metastases and Treatment
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- DNA and Nucleic Acid Chemistry
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Carcinogens and Genotoxicity Assessment
- Chromatin Remodeling and Cancer
- Biochemical and Molecular Research
- Urological Disorders and Treatments
- Renal cell carcinoma treatment
- FOXO transcription factor regulation
- Tuberous Sclerosis Complex Research
- Cancer Immunotherapy and Biomarkers
- Polyomavirus and related diseases
Science for Life Laboratory
2018-2023
Bristol-Myers Squibb (United States)
2020-2023
Karolinska Institutet
2018-2023
The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG because Ogg1-deficient mice are resistant acute systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention treatment inflammation. We developed TH5487, selective active-site inhibitor OGG1, which hampers binding repair well tolerated by...
Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease (APE1) and initiating repair. Here, we describe small molecule (TH10785) that interacts with the phenylalanine-319 glycine-42 amino acids of OGG1, increases enzyme activity 10-fold, generates previously undescribed β,δ-lyase enzymatic function. TH10785 controls catalytic mediated nitrogen base within its molecular structure. In cells, OGG1...
•Bromodomain and extra-terminal domain (BET) proteins may play a pivotal role in cancer.•CC-90010 is potent, reversible, oral BET inhibitor with long terminal half-life, which enables less frequent dosing.•CC-90010 was well tolerated had encouraging antitumor activity heavily pretreated patients advanced malignancies. BackgroundBromodomain are epigenetic readers that regulate expression of genes involved oncogenesis. CC-90010 novel, oral, small-molecule inhibitor.Patients...
Abstract Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target exploit reactive oxygen species (ROS) elevation cancer. Although depletion is well tolerated non-transformed cells, report here...
The most common oxidative DNA lesion is 8-oxoguanine which mainly recognized and excised by the 8-oxoG glycosylase 1 (OGG1), initiating base excision repair (BER) pathway. Telomeres are particularly sensitive to stress (OS) disrupts telomere homeostasis triggering genome instability. In present study, we have investigated effects of inactivating BER in OS conditions, using a specific inhibitor OGG1 (TH5487). We found that TH5487 blocks initiation at telomeres causing an accumulation oxidized...
Abstract Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, may a role cancer-cell proliferation, survival, oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study trotabresib, oral BET inhibitor, heavily pretreated patients with advanced solid tumors relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, RP2D trotabresib. Secondary clinical...
Abstract Background The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, CNS penetration of recurrent gliomas scheduled for salvage resection. Methods Patients received 30 mg/day on days 1–4 before surgery, followed by maintenance 45 4 on/24 off after surgery. Primary...
8-oxoguanine DNA glycosylase (OGG1) is the main responsible for excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex to initiate base repair. This activity relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding role OGG1, we previously reported TH5487, potent active site inhibitor OGG1. Here, further investigate consequences inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation genomic 8-oxoG...
DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs oxidative order to maintain genomic integrity. In mammals, eleven glycosylases have been reported initiate BER, where each recognizes a few related substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one most abundant lesions, recognized and excised mainly 8-oxoguanine glycosylase 1 (OGG1)....
Abstract Background Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain extraterminal inhibitor, demonstrated antitumor activity in patients high-grade gliomas. Methods In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, 45 mg combined TMZ the adjuvant...
Abstract The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate but a biological significance for this biochemical reaction has not yet been established. Glucose-1-phosphate is an important metabolite energy biomass production through glycolysis nucleotides required DNA replication are produced energetically expensive de novo or energy-efficient salvage pathways. Here, we describe p53-regulated NUDT22-dependent hydrolysis...
Abstract Trotabresib (CC-90010) demonstrated antitumor activity as monotherapy in patients with advanced malignancies (Moreno et al. ESMO 2020. 5270) and enhanced the antiproliferative effects of temozolomide preclinical studies. CC-90010-GBM-002 (NCT04324840) is a phase 1B dose-finding study investigating standard-of-care + radiotherapy followed by adjuvant trotabresib or concomitant temozolomide, post-resection, newly diagnosed glioblastoma. We present interim results for temozolomide....
Abstract Background: BET proteins are epigenetic readers and activators of oncogenic pathways in cancer. CC-95775 is a novel oral small molecule bromodomain inhibitor. It non-specific inhibitor with potent activity against all 4 family members (BRD2, BRD3, BRD4, BRDT), shows additional towards several non-BET proteins. Methods: CC-95775-ST-001 phase 1 dose-escalation study patients advanced STs. Primary objectives were to determine safety recommended 2 dose (RP2D). Secondary exploratory...
3015 Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth oncogenesis. CC-90010 is an oral, potent reversible BET inhibitor showed promising activity lymphoma solid tumor lines reduced xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) a phase I, first-in-human study patients (pts) with advanced tumors R/R NHL. Three schedules 11 dose levels were evaluated (Table). Primary objectives to...
A 66-year-old female presented with a urethral caruncle. Histological features of incomplete intestinal metaplasia were reported. Only five previous cases in caruncles have been The mechanism this tissue transformation remains unclear but theorised aetiologies include embryological and infective causes. Intestinal carries malignant potential other organs, most notably the bladder. Therefore we recommend be completely excised prolonged follow up for atypical variants.
Abstract The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate 1 . Glucose-1-phosphate is an important metabolite for energy biomass production through glycolysis subsequent tricarboxylic acid (TCA) cycle nucleotides required DNA replication are produced energetically expensive de novo or energy-efficient salvage pathways 2 Here, we describe p53-regulated NUDT22-dependent hydrolysis of to maintain cancer cell growth...
Abstract Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity blood–brain barrier penetration in patients with high-grade gliomas, enhanced the antiproliferative effects of temozolomide preclinical models. CC-90010-GBM-002 (NCT04324840) is phase 1b/2 study investigating addition trotabresib to standard-of-care (SOC) concomitant plus radiotherapy adjuvant temozolomide, followed by maintenance trotabresib, newly diagnosed glioblastoma. The...
Due to oncogene expression and altered metabolism, reactive oxygen species (ROS) production is augmented in cancer cells resulting oxidative DNA damage. 8‑oxoguanine (8-oxoG) one of the most abundant lesions. This premutagenic lesion eliminated from duplex by 8‑Oxoguanine Glycosylase (OGG1), a key player base excision repair (BER) pathway. Here, we validate OGG1 as potential anti-cancer target. depletion impairs growth A3 T-cell lymphoblastic acute leukemia both vitro vivo, but well...