A5000427124- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Cancer therapeutics and mechanisms
- Hepatitis B Virus Studies
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Molecular Research
- Nuclear Receptors and Signaling
- Acute Myeloid Leukemia Research
- Cancer Genomics and Diagnostics
- DNA Repair Mechanisms
- Cytokine Signaling Pathways and Interactions
- Bioactive Compounds and Antitumor Agents
- Chronic Lymphocytic Leukemia Research
- Cancer-related Molecular Pathways
- DNA and Nucleic Acid Chemistry
- Epigenetics and DNA Methylation
- Computational Drug Discovery Methods
- Synthesis of Tetrazole Derivatives
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Carbohydrate Chemistry and Synthesis
- Multiple Myeloma Research and Treatments
- Genomics and Chromatin Dynamics
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
WuXi AppTec (China)
2016-2023
University of California, San Francisco
2022-2023
Broad Center
2022-2023
UCSF Helen Diller Family Comprehensive Cancer Center
2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
2009-2016
Inhibition of the bromodomain transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed vivo chemical tool 1 (GNE-272) for CBP that was moderately potent and selective over BRD4(1). In pursuit a more inhibitor, we used structure-based design. Constraining aniline into tetrahydroquinoline motif maintained potency increased selectivity 2-fold. Structure–activity relationship studies coupled with further design targeting LPF...
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target much recent interest in cancer and immune system regulation. A co-crystal structure ligand-efficient screening hit CBP guided initial design targeting LPF shelf, ZA loop, acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify more potent analogue. Optimization permeability microsomal stability subsequent improvement mouse hepatocyte afforded 59 (GNE-272,...
Abstract Background Enhancers are essential in defining cell fates through the control of cell-type-specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and histone modifiers including monomethylation H3K4 (H3K4me1) by MLL3 (KMT2C) MLL4 (KMT2D). MLL3/4 thought to be critical for enhancer cognate expression recruitment acetyltransferases H3K27. Results Here we test this model evaluating impact loss on transcription during early differentiation...
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward second generation culminated the discovery of narlaprevir 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, II human Exploration synthetic sequence for preparation 37 resulted route that required no silica gel purification entire synthesis.
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, affects more than 200 million people worldwide. Although combination therapy interferon-alpha ribavirin reasonably successful in treating majority genotypes, its efficacy against predominant genotype (genotype 1) moderate at best, with only about 40% patients showing sustained virological response. Herein, SAR discovery a series ketoamide derived P(1)-P(3)...
The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. moderate efficacy along with side effects the current pegylated interferon and ribavirin combination therapy underscores need for more effective safer new treatment. In an effort to improve upon our clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on P3 capping moieties. This led discovery tert-leucinol derived cyclic imides as potent series novel groups. Thus, introduction...
Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of indole core. The best C-5 groups found to be compact and nonpolar moieties that C-6 attachments not affecting potency. Limited N-1 benzyl-type substituent indicated substitutions fluoro or methyl 2' 5' benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides incorporated as acid isosteres C-2 position. Further optimization combination...
The NS3 protease of hepatitis C virus (HCV) has emerged as one the best characterized targets for next-generation HCV therapy. tetrapeptide 1 and pentapeptide 2 are alpha-ketoamide-type serine inhibitors with modest potency. We envisioned that 1,2,3,4-tetrahydroisoquinoline-3-carboxylamide (Tic) moiety could be cyclized to P3 capping group. resulting macrocycle enhance binding through its extra contact Ala156 methyl Macrocyclization also provide a less peptidic inhibitor. Synthesis started...
The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice intensive drug discovery research. On the basis an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from P2 proline to P3 capping could enhance binding backbone Ala156 residue and S4 pocket. Thus, number proline-based macrocyclic α-ketoamide inhibitors were prepared investigated in HCV serine continuous assay (Ki*). biological activity varied substantially...
Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to discovery irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation a covalent bond adjacent cysteine-366 thiol was proved by mass spectroscopy and X-ray crystal structure studies. C-5 ethyl C-2...
Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy.
Hepatitis C is the most prevalent liver disease. Viral hepatitis (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at 56th Annual Meeting American Association for Study Liver Diseases (AASLD) were encouraging, and thus, additional human are underway. In view positive data from compound, further work aimed optimizing its overall profile...
The limited efficacy and considerable side effects of currently available therapies for the treatment hepatitis C virus (HCV) infection have prompted significant efforts toward development safe effective new therapeutics. pentapeptide α-ketoamides type 1 were weak HCV inhibitors with a binding constant, Ki*, above 5 μM. We envisioned that cyclization P2 phenyl chain to P3 capping group could enhance through an interaction resulting macrocycle methyl Ala156 on enzyme backbone. macrocyclic...
Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), novel, potent, selective, orally bioavailable NS3 protease inhibitor that currently undergoing phase III clinical trials. Our efforts toward second generation HCV serine were directed at improving overall profile inhibitor. This article will elaborate on our studies new P4 modified...
Life-saving donut: Macrocyclization through a Mitsunobu reaction was used to synthesize 17-membered macrocycle. The bicyclic acetal core prepared completely diastereoselectively. macrocyclic peptidomimetic surrogate of the P2–P3 dipeptide moiety designed function as hepatitis C virus (HCV) NS3 serine protease inhibitor, and pentapeptide α-ketoamides derived from macrocycle were shown be potent HCV inhibitors. Supporting information for this article is available on WWW under...