Liping H. Pettus
A5069660930- Cancer-related gene regulation
- Cancer Mechanisms and Therapy
- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Protein Kinase Regulation and GTPase Signaling
- Phytochemical compounds biological activities
- Synthesis and Catalytic Reactions
- PI3K/AKT/mTOR signaling in cancer
- Chemical synthesis and alkaloids
- Synthesis of Indole Derivatives
- Traditional and Medicinal Uses of Annonaceae
- Chronic Lymphocytic Leukemia Research
- Cancer therapeutics and mechanisms
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Bioactive Compounds and Antitumor Agents
- Computational Drug Discovery Methods
- Quinazolinone synthesis and applications
- Multicomponent Synthesis of Heterocycles
- Biochemical and Molecular Research
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Ion Channels and Receptors
Amgen (United States)
2011-2025
Rensselaer Polytechnic Institute
1997-2005
University of California, Santa Barbara
2000-2004
University of Rochester
1998-1999
The development and optimization of a series quinolinylpurines as potent selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification 1 (AMG319), compound an IC50 16 nM in human whole blood assay (HWB), selectivity over large panel protein kinases, high level vivo efficacy measured by two rodent disease models inflammation.
One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 cancer cells with MTAP deletion. We report discovery clinical stage MTA-cooperative inhibitor AMG 193, which preferentially binds presence MTA and potent biochemical cellular activity MTAP-deleted across lineages. In vitro, inhibition induces DNA damage, cell cycle arrest, aberrant alternative mRNA splicing cells. human line patient-derived xenograft models, 193...
The highly diastereoselective potassium in ammonia reduction−ethylation (EtI) of the chiral 2-(trimethylsilyl)benzamide 1b to give 1,4-cyclohexadiene 3 is key step asymmetric syntheses (−)-eburnamonine (4) and (−)-aspidospermidine (5). Cyclohexadiene was converted cyclohexanone 7, which provided trimethylsilyl-substituted butyrolactone 9 utilized for synthesis 4 13 required 5. preparation depended upon completely regioselective silicon-directed Baeyer−Villiger oxidation 7 → 8; cyclohexenone...
A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade capsaicin or acid-induced influx calcium into CHO cells expressing TRPV1. The investigation structure−activity relationships heterocyclic A-region revealed optimum pharmacophoric elements required for activity this and resulted identification subnanomolar antagonists. most potent these were thoroughly profiled pharmacokinetic assays. Optimization led to design synthesis 23, a compound that...
Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting CIN-associated vulnerabilities an emerging therapeutic strategy drug development. KIF18A, mitotic kinesin, has been shown to play role maintaining bipolar spindle integrity and promotes viability CIN cells. To explore the potential series inhibitors was identified. Optimization initial hit led discovery analogues could be used as chemical probes interrogate...
<p>Supplementary Methods: SDMA Imaging Assay, ELISA, Immunohistochemistry</p>
<p>Supplementary Figure S6. AM-9747 treatment results in increased DNA damage and cellular senescence BxPC-3 cells</p>
<p>Supplementary Figure S8. AMG 193 treatment in BxPC-3 tumors does not affect circulating blood cells</p>
<p>Supplementary Figure S5. <i>In vitro</i> target validation, RNA-seq, and additional cell cycle data in WT MTAP-deleted tumor cells</p>
<p>Supplementary Figure S2. SPR AMG 193 competitive chaser experiment</p>
<p>Supplementary Figure S3. HCT116 isogenic pair validation</p>
<p>Supplementary Figure S1. SPR chaser characterization</p>
<p>Supplementary Figure S7. Time course SDMA analysis, CDX models versus AMG 193, and AM-9747 PDX trial</p>
<p>Supplementary Figure S10. AMG 193 and sotorasib combination is synergistic in the MIAPACA2 MTAP–deleted, KRAS G12C mutant cell line</p>
<p>Supplementary Figure S9. AMG 193 chemotherapy combinations are synergistic in the H292 MTAP-deleted NSCLC cell line</p>
<div>Abstract<p>One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on protein arginine methyltransferase 5 (PRMT5) cancer cells with <i>MTAP</i> deletion. We report discovery clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds presence MTA and potent biochemical cellular activity MTAP-deleted across lineages. <i>In vitro</i>, inhibition induces DNA damage,...
<p>Supplementary Figure S11: AMG 193 treatment of patients with MTAP-deleted cancers results in inhibition serum SDMA</p>
<p>Supplementary Figure S4. AM-9747 preferentially inhibits viability and SDMA signaling in MTAP-deleted tumor cells</p>