A5083564215- interferon and immune responses
- Cancer Immunotherapy and Biomarkers
- Salivary Gland Tumors Diagnosis and Treatment
- Virus-based gene therapy research
- RNA modifications and cancer
- Prostate Cancer Treatment and Research
- Hedgehog Signaling Pathway Studies
- Cancer Cells and Metastasis
- Cancer Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- Cystic Fibrosis Research Advances
- Cytokine Signaling Pathways and Interactions
- Developmental Biology and Gene Regulation
- Estrogen and related hormone effects
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Lung Cancer Research Studies
- Head and Neck Anomalies
- Ferroptosis and cancer prognosis
- Adenosine and Purinergic Signaling
- Cancer, Lipids, and Metabolism
- Peptidase Inhibition and Analysis
- Cancer Genomics and Diagnostics
- Immune Cell Function and Interaction
- Chromatin Remodeling and Cancer
- Immune cells in cancer
Merck & Co., Inc., Rahway, NJ, USA (United States)
2011-2024
Quantitative BioSciences
2020-2021
Pharmacological activation of the STING (stimulator interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report identification MSA-2, an orally available non-nucleotide human agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated stimulated interferon-β secretion in tumors, induced regression with durable antitumor immunity, synergized anti-PD-1 therapy. Experimental theoretical analyses showed...
Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed synthesized to access a previously unexplored chemical space. The assessment biochemical affinity cellular potency, along with computational, structural, biophysical characterization, was applied influence the design optimization novel STING agonists, resulting in discovery MK-1454 as molecule appropriate properties for clinical development. When administered...
Abstract Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading constitutive receptor activation were confined triple-negative breast cancers (TNBC; 6 66 tumors). TNBC cell lines with associated high levels activated (N1-ICD) sensitive the gamma-secretase inhibitor (GSI) MRK-003, both alone combination paclitaxel, vitro vivo, whereas resistant GSI. Immunohistochemical staining N1-ICD xenografts...
Androgen receptors have been shown to play a critical role in prostate cancer. We used ultrasound imaging techniques track tumor response antiandrogen and rapamycin treatment prostate-specific Pten-deleted mouse model of Depletion androgens by either surgical or chemical castration significantly inhibited growth progression without altering the activation Akt mammalian target (mTOR). also showed for first time that targeting mTOR along with exhibited additive antitumor effects vivo when...
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is negative regulator of signal transduction in immune cells, including T B and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition the anti-tumor response associated with functional augmentation cells. We have used potent, small molecule inhibitor, Compound 1, to investigate effects pharmacological intervention activity enhanced Th1 cytokine production fully...
Hematopoietic progenitor kinase 1 (HPK1), also referred to as mitogen-activated protein (MAP4K1), is a serine/threonine that negatively regulates T-cell signaling by phosphorylating Ser376 of Src homology 2 (SH2) domain-containing leukocyte 76 kDa (SLP-76), critical mediator receptor activation. HPK1 loss function mouse models demonstrated enhanced immune cell activation and beneficial antitumor activity. To enable discovery functional characterization high-affinity small-molecule...
Meeting abstracts LAG-3 has been shown to act as an inhibitory molecule involved in the regulation of T cell activation, proliferation and homeostasis. Exhausted populations that evolve tumor microenvironment or during chronic viral infections show coordinated expression
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been reported to mediate both tumorigenic and anti-tumor effects in vivo. Blockade of the CEACAM1 signaling pathway recently implicated as a novel mechanism for cancer immunotherapy. CC1, mouse anti-CEACAM1 monoclonal antibody (mAb), widely used pharmacological tool preclinical studies inform on biology although limited data are available its blocking characteristics or pharmacodynamic-pharmacokinetic profiles. We sought...
The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel agonist, MSA-1, activates both mouse human with higher in vitro potency than cGAMP. Following intratumoral administration MSA-1 to panel syngeneic tumors...
Abstract The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism we synthesized a novel agonist, MSA-1, activates both mouse human with higher in vitro potency than cGAMP. MSA-1 was administered to immune-competent mice...
Abstract Target validation can be challenging when mouse efficacy studies require achieving a high therapeutic exposure of tool compound, ideally with low peak-to-trough (P/T) ratio to avoid Cmax-induced toxicity. Herein, we describe the daily co-administration CYP inhibitor aminobenzotriazole (ABT) as well-tolerated PK enhancer for medium-term in mice, enabling faster decision-making early space imperfect tools. Genetic mice have suggested that HPK1 inhibition would lead enhanced effector...
Supplementary Figures 1-4 from Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in a <i>Pten</i>-Deficient Mouse Model Prostate Cancer
Supplementary Figures 1-4 from Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in a <i>Pten</i>-Deficient Mouse Model Prostate Cancer
<p>Supplemental Table 1: Log2Ratio and p values for all 310 genes shown in Figure 6</p>
<p>Supplemental Figure 1: Day 10 tumor volume of injected (InjT) and noninjected (Non-injT) tumors following intratumoral (IT) injection with MSA-1</p>
<p>File includes genomic analysis, cell cycle and proliferation analysis.</p>
<p>S1: NOTCH gene rearrangement in breast cancer cell lines and human tumors. S2: sensitivity to MRK-003. S3: HES4 expression is associated with gene-rearrangement or activating mutation NOTCH. S4: a poor prognostic marker TNBC. S5: Proliferation inhibition by combination therapy MRK-003 ERK inhibitor (SCH772984). S6: Effect of treatment on CD44+/CD24 high stem-like population. S7: N1ICD level correlates status predictive response xenograft models.</p>
<p>Supplemental Figure 2: STING agonists stimulate cytokines in tumor, plasma and peripheral tissues following IT dosing.</p>
<p>Supplemental Figure 3: MC38 tumor growth in C57BL/6, Nude or NSG mice and comparison of systemic cytokines</p>
<p>Supplementary Methods and Figures</p>
<p>Supplemental Table 1: Log2Ratio and p values for all 310 genes shown in Figure 6</p>