A5027692068- PARP inhibition in cancer therapy
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Synthesis and Catalytic Reactions
- DNA Repair Mechanisms
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Monoclonal and Polyclonal Antibodies Research
- Metal complexes synthesis and properties
- Synthetic Organic Chemistry Methods
- Radiation Therapy and Dosimetry
- Peptidase Inhibition and Analysis
- Health, Environment, Cognitive Aging
- Biochemical and Molecular Research
- RNA modifications and cancer
- Asymmetric Synthesis and Catalysis
- Innovation Policy and R&D
- Cancer, Hypoxia, and Metabolism
- Phenothiazines and Benzothiazines Synthesis and Activities
- Malaria Research and Control
- Hepatitis B Virus Studies
- Epigenetics and DNA Methylation
- Advanced Synthetic Organic Chemistry
Tango Therapeutics (United States)
2021-2025
Vertex Pharmaceuticals (United States)
2004-2017
Johns Hopkins University
2000-2003
It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if inhibitors leverage consequence deletion, namely, accumulation substrate MTA. Herein, we describe discovery TNG908, a potent inhibitor binds PRMT5·MTA complex, leading to 15-fold-selective killing MTAP-deleted (MTAP-null) compared MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its...
The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring approximately 10–15% all human cancer. We have previously described discovery TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which present elevated concentrations cells. Herein we describe TNG462, more potent selective MTA-cooperative inhibitor improved DMPK properties cancers currently Phase...
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...
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...
Deletion of the MTAP gene leads to accumulation substrate protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition PRMT5•MTA complex relative PRMT5•SAM can lead killing cancer cells deletion. Herein, we describe discovery novel compounds using structure-based drug design switch mechanism binding known, SAM-cooperative inhibitors an MTA-cooperative by occupying portion SAM pocket in that is unoccupied when bound hydrogen...
Abstract Treatment of brain tumors and metastases remains a significant unmet medical need. This is especially true for high-grade gliomas, where up to 50% cases exhibit loss MTAP, creating dependency on PRMT5 susceptibility MTA-cooperative inhibitors. For preclinical drug discovery, the accurate prediction exposure in human CNS compartment therefore critical importance. study evaluates utility models, specifically monkey cerebrospinal fluid (CSF) model, alongside physicochemical properties...
<p>Supplementary Figure S3 shows CRISPR screening data suggesting that loss of the BRCA1-A complex sensitizes cells to TNG348, but not olaparib</p>
<p>Supplementary Figure S4 shows additional data supporting 4. This includes an alternative representation for the combination cell line panels shown in 4D-E, examples of between TNG348 and saruparib, olaparib, cisplatin or SN38, viability effects MCF10A TNG348, RP3500 ART558 alone with olaparib.</p>
<p>Supplementary Figure S5 shows additional data supporting 5 including mouse body weight following TNG348, PARPi or combination treatment, in vivo experiments with lower TNG348 doses, an experiment a BRCA1/2wt PDX model, and plasma concentration comparisons between alone versus their combination.</p>
<p>Supplementary methods include the chemical synthesis procedure of TNG348 and additional biochemical assay protocols not included in main text.</p>