A5057303784- interferon and immune responses
- Cancer Immunotherapy and Biomarkers
- Tryptophan and brain disorders
- Pharmacogenetics and Drug Metabolism
- Virus-based gene therapy research
- Monoclonal and Polyclonal Antibodies Research
- Chronic Lymphocytic Leukemia Research
- Pharmacological Receptor Mechanisms and Effects
- RNA modifications and cancer
- Immunodeficiency and Autoimmune Disorders
- Cancer, Hypoxia, and Metabolism
- Bipolar Disorder and Treatment
- bioluminescence and chemiluminescence research
- Cancer Research and Treatments
- Drug-Induced Hepatotoxicity and Protection
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cytokine Signaling Pathways and Interactions
- Computational Drug Discovery Methods
- Adenosine and Purinergic Signaling
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Receptor Mechanisms and Signaling
- Analytical Chemistry and Chromatography
- Synthetic Organic Chemistry Methods
- Immune cells in cancer
Merck & Co., Inc., Rahway, NJ, USA (United States)
2014-2024
United States Military Academy
2022
WuXi AppTec (China)
2016-2020
Boston University
2014
GTx (United States)
1999
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 Matrix‐assisted laser desorption/ionization hyphenated with quadrupole time‐of‐flight (QTOF) mass spectrometry (MS) has been used to directly determine the distribution of pharmaceuticals in rat brain tissue slices which might unravel their disposition for new drug development. Clozapine, an antipsychotic drug, and norclozapine were as model compounds investigate fundamental parameters such matrix solvent effects irradiance dependence on MALDI intensity but also address issues...
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types cancers. However, low overall response rates often hamper the broad utility potential these breakthrough therapies. Combination therapy strategies currently under intensive investigation in clinic, including combination PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report discovery a class heme-binding featuring unique amino-cyclobutarene motif, which was discovered...
Bruton's tyrosine kinase (BTK) is a Tec family with well-defined role in the B cell receptor (BCR) pathway. It has become an attractive target for selective inhibition and treatment of related diseases. We report series compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors excellent selectivity. Selectivity achieved through specific interactions ligand hinge driven by aminopyridine hydrogen bondings Ser538 Asp539, hydrophobic interaction...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field cancer immunotherapy, upregulation IDO1 in certain cancers been linked host immune evasion and poor prognosis for patients. In particular, inhibition is combination therapy with checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, diamide class compounds was identified promising lead IDO1. While hit 1 possessed attractive cell-based potency, it suffered from...
Abstract Early risk assessment of drug-induced liver injury (DILI) potential for drug candidates remains a major challenge pharmaceutical development. We have previously developed set rat transcriptional biomarkers in short-term toxicity studies to inform the generate high burden chemically reactive metabolites that presents higher human DILI. Here, we describe translation those NRF1-/NRF2-mediated tissue an vitro assay using advanced micropatterned coculture system (HEPATOPAC) with primary...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this compounds. Structure-based drug design strategic incorporation polarity enabled rapid improvement on potency, solubility, oxidative metabolic stability. Metabolite studies revealed that amide hydrolysis in D-pocket was...
The aim of this article is to focus on the implementation and application matrix-assisted laser desorption/ ionization-imaging mass spectrometric system (MALDI-IMS) determine disposition or biotransformation pathway terfenadine its active metabolite, fexofenadine in mouse rat whole-body tissue sections. Whole-body MALDI-IMS data showed that poor oral bioavailability was largely due high first-pass metabolism intestines liver before compound reached systemic circulation.
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable Q3W (once every 3 weeks) oral parenteral dosing. A diamide IDO was discovered through an automated ligand identification system (ALIS). Installation fluorophenyl dramatically improved potency. Identification biaryl moiety unconventional amide isostere addressed metabolic...
A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated number metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities FIXa protein. Microgram quantities interest then isolated through microisolation analytical capabilities, structurally characterized using MicroCryoProbe heteronuclear 2D NMR...
Hepatocellular accumulation of bile salts by inhibition salt export pump (BSEP/ABCB11) may result in cholestasis and is one proposed mechanism drug-induced liver injury (DILI). To understand the relationship between BSEP DILI, we evaluated 64 DILI-positive 57 DILI-negative compounds BSEP, multidrug resistance protein (MRP) 2, MRP3, MRP4 vesicular assays. An empirical cutoff (5 μM) for was established based on a IC50 values calculated maximal unbound concentration at inlet human (fu*Iin,max,...
Herein we report the discovery and hit-to-lead optimization of a series spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, lead-like physical pharmacokinetic properties.
The science of drug discovery involves multiparameter optimization molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation each individual compound, gravimetric quantitation, and preparation a standard concentration solution for biological assays. In this work, we explore ways to expedite process by testing unpurified mixtures using combination mass spectrometry-based assays affinity selection...
Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series improve their metabolic stability potency. Enabling synthetic chemistry was developed construct these unique fused cyclopropyl compounds, leading improved pharmacokinetics whole blood potency a oral as 9 mg once daily (QD).
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...