A5040096797- PARP inhibition in cancer therapy
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Chromatin Remodeling and Cancer
- Nuclear Structure and Function
- Protein Tyrosine Phosphatases
- PI3K/AKT/mTOR signaling in cancer
- Galectins and Cancer Biology
- Sarcoma Diagnosis and Treatment
- Science, Research, and Medicine
- Cancer Mechanisms and Therapy
- CRISPR and Genetic Engineering
- Protein Kinase Regulation and GTPase Signaling
- Multiple Myeloma Research and Treatments
- RNA modifications and cancer
- Cancer-related gene regulation
- Cancer Genomics and Diagnostics
- RNA Research and Splicing
- Cancer-related Molecular Pathways
- Advanced Proteomics Techniques and Applications
- DNA Repair Mechanisms
- interferon and immune responses
- Health, Environment, Cognitive Aging
- Neuroblastoma Research and Treatments
- Liver physiology and pathology
Tango Therapeutics (United States)
2021-2025
Xilio Therapeutics (United States)
2019
The University of Texas MD Anderson Cancer Center
2014-2018
AMAG Pharmaceuticals (United States)
2018
Merck & Co., Inc., Rahway, NJ, USA (United States)
1995-2016
The University of Texas Health Science Center at Houston
2015
Epix Pharmaceuticals (United States)
2015
Dana-Farber Cancer Institute
1989-2011
Cold Spring Harbor Laboratory
2000-2011
Merck (Japan)
2009-2011
The SWI/SNF multisubunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF-mutant tumors, including SMARCA4-deficient lung cancer; however, contribution conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct SMARCA2/4 paralog dependence...
Phosphorylation sites on proteins in the phosphatidylinositol 3-kinase pathway that are regulated by candidate drugs can serve as useful biomarkers to predict tumor sensitivity AKT inhibitors.
Abstract Background Hyperactivation of the Ras signaling pathway is a driver many cancers, and RAS activation can predict response to targeted therapies. Therefore, optimal methods for measuring are critical. The main focus our work was develop gene expression signature that predictive dependence. Methods We used coherent pathway-related genes across multiple datasets derive generate scores in pre-clinical cancer models human tumors. then related this KRAS mutation status drug data clinical...
The bromodomain containing proteins TRIM24 (tripartite motif protein 24) and BRPF1 (bromodomain PHD finger 1) are involved in the epigenetic regulation of gene expression have been implicated human cancer. Overexpression correlates with poor patient prognosis, is a scaffolding required for assembly histone acetyltransferase complexes, where MOZ (monocytic leukemia zinc protein) was first identified as recurrent fusion partner patients (8p11 chromosomal rearrangements). Here, we present...
Abstract CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors subset wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition leads to decreased synthesis concomitant S-phase–specific damage. Genome-wide CRISPR-Cas9 screens identify RAD18 UBE2K, which promote...
Abstract Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for treatment BRCA1/2 mutant cancers, potentially including patients whose have primary or acquired resistance to PARP inhibitors (PARPi). Here, we present comprehensive characterization TNG348, an allosteric, selective, reversible inhibitor (USP1i). TNG348 induces dose-dependent accumulation...
// Patrycja Czerwińska 1, 2, 3 , Parantu K. Shah 4 Katarzyna Tomczak Marta Klimczak Sylwia Mazurek Barbara Sozańska 5 Przemysław Biecek 5, 6 Konstanty Korski 7 Violetta Filas Andrzej Mackiewicz 2 Jannik N. Andersen Maciej Wiznerowicz 1 Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Centre, Poznan, Chair Medical Biotechnology, Poznan University Sciences, Postgraduate School Molecular Medicine, Warsaw, Institute Applied Science, Texas MD Anderson...
Abstract Synthetic lethality is a genetic interaction that results in cell death when two deficiencies co-occur but not either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic–lethal interactions by virtue their redundant functions. Here, we demonstrate paralog-based synthetic targeting vaccinia-related kinase 1 (VRK1) glioblastoma (GBM) deficient VRK2, silenced promoter methylation...
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and potential drug target for the treatment type 2 diabetes other associated metabolic syndromes. To further define role PTP1B in to test hypothesis that blocking activity would augment action insulin, we prepared several cell permeable, potent selective, small molecule inhibitors, evaluated their biological effects sensitive lines. Our data indicate inhibitors bind colocalize...
Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 therapeutic target, pharmacological support lacking due to the prevalence nonspecific inhibitors. Here, we benchmark literature newly developed inhibitors conduct parallel genetic queries into function in cancer cells. Through selectivity profiling x-ray crystallographic...
Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein histone PTMs their regulatory outcomes have been reported, but little is known about how proteins may in turn be modulated by these interactions. Tripartite motif–containing 24 (TRIM24) a aberrantly expressed multiple cancers. Here, our investigation revealed functional cross-talk acetylation TRIM24...
The phosphoinositide 3-kinase/AKT signaling pathway plays a key role in cancer cell growth, survival, and angiogenesis. Phosphoinositide-dependent protein kinase-1 (PDK1) acts at focal point this immediately downstream of 3-kinase PTEN, where it phosphorylates numerous AGC kinases. PDK1 kinase domain has least three ligand-binding sites: the ATP-binding pocket, peptide substrate-binding site, groove N-terminal lobe that binds C-terminal hydrophobic motif its substrates. Based on unique...
Proteins that 'read' the histone code are central elements in epigenetic control and bromodomains, which bind acetyl-lysine motifs, increasingly recognized as potential mediators of disease states. Notably, first BET bromodomain-based therapies have entered clinical trials there is a broad interest dissecting therapeutic relevance other bromodomain-containing proteins human disease. Typically, drug development facilitated expedited by high-throughput screening, where assays need to be...
Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy tolerability it is highly desirable improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis optimization. Here, using bromodomain extra-terminal (BET) protein...
Chromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion neighboring genes. This collateral damage can create novel dependencies specific the co-deleted context. One notable example is dependency on PRMT5 activity tumors with MTAP deletion, which co-occurs CDKN2A/B loss, development MTA-cooperative inhibitors. To identify additional context/target pairs for chromosome 9p and other common loci chromosomal deletions, we conducted a...