A5023242962- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- Synthesis and biological activity
- Cytokine Signaling Pathways and Interactions
- Genetics, Aging, and Longevity in Model Organisms
- Peptidase Inhibition and Analysis
- Protein Kinase Regulation and GTPase Signaling
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Advanced Fluorescence Microscopy Techniques
- Reproductive Biology and Fertility
- Liver physiology and pathology
- Advanced Electron Microscopy Techniques and Applications
- Synthesis and Characterization of Heterocyclic Compounds
- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Chronic Lymphocytic Leukemia Research
- Phytochemical compounds biological activities
- Computational Drug Discovery Methods
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Biochemical and Molecular Research
- CRISPR and Genetic Engineering
- Single-cell and spatial transcriptomics
Berkeley College
2024
University of California, Berkeley
2024
Nurix (United States)
2019-2020
Novartis (Switzerland)
2014
Novartis Institutes for BioMedical Research
2014
Pathways Behavioral Services
2014
University of California, Davis
1999-2006
Abstract Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in development small molecules that modulate these interactions; however, rational design molecule enhancers PPIs remains elusive. Herein, we report prospective identification and potent enhance interaction between an oncogenic transcription factor, β-Catenin, its cognate ligase, SCF β-TrCP . These...
Abstract Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies. Experimental Design: Pan-PIM proven difficult develop because PIM2 low Km for ATP and, thus, requires very...
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans assess whether pan PIM inhibition may provide benefit cancer patients. Herein, the synthesis, vitro activity, vivo activity an acute myeloid xenograft model, preclinical profile potent selective inhibitor compound 8 (PIM447) are described. Starting from reported aminopiperidyl 3, a strategy improve microsomal stability was pursued resulting identification...
The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety cancers and its substrate phosphorylation has been implicated direct regulation cell survival, proliferation, polarity. This study characterizes presents the most selective potent RSK inhibitors known to date, LJH685 LJI308. Structural analysis confirms binding RSK2 N-terminal ATP-binding site reveals that inhibitor adopts an unusual nonplanar conformation explains excellent selectivity for...
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, full understanding of this restricted by lack highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor N-terminal RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted optimized difluorophenol pyridine inhibitors RSK demonstrated cellularly inhibition YB1 phosphorylation. These...
The PAR proteins are required for polarity and asymmetric localization of cell fate determinants in C. elegans embryos. In addition, several the conserved localized asymmetrically polarized cells Drosophila, Xenopus mammals. We have previously shown that ooc-5 ooc-3 mutations result defects spindle orientation early particular, these genes affect re-establishment protein asymmetry P1 two-cell now report encodes a putative ATPase Clp/Hsp100 AAA superfamilies proteins, with highest sequence...
Abstract Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase survival. However, mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination a inhibitor to examine within nuclei living cells. inhibition traps chromatin, requiring p97/VCP extraction and...
Abstract Single-molecule localization microscopy (SMLM) techniques, such as single-molecule tracking (SMT), enable in situ measurements cells from which data-rich metrics can be extracted. SMT has been successfully applied to a variety of biological questions and model systems, aiming unravel the spatiotemporal regulation molecular mechanisms that govern protein function, downstream pathway effects, cellular function. While powerful, SMLM often suffers low throughput illumination...
Abstract Single-molecule localization microscopy (SMLM) techniques, such as single-molecule tracking (SMT), enable in situ measurements cells from which data-rich metrics can be extracted. SMT has been successfully applied to a variety of biological questions and model systems, aiming unravel the spatiotemporal regulation molecular mechanisms that govern protein function, downstream pathway effects, cellular function. While powerful, SMLM often suffers low throughput illumination...
<p>PDF file - 346KB, Supplementary Figure 1. Normal vs. Tumor expression of PIM kinases mRNA across 17 tissue types. 2. Comparison LGB321 on-target activity Previously described pan-PIM inhibitor. 3. KINOMESCANTM 1 mu M LGB321. 4. Biochemical and cellular selectivity the inhibitor series towards GSK3 beta. 5. does not inhibit EGFR signaling in HCC1954 cells. Table Sensitivity to Erlotinib Lung Cells CCLE. hematological malignacies cell lines.</p>
<p>PDF file - 346KB, Supplementary Figure 1. Normal vs. Tumor expression of PIM kinases mRNA across 17 tissue types. 2. Comparison LGB321 on-target activity Previously described pan-PIM inhibitor. 3. KINOMESCANTM 1 mu M LGB321. 4. Biochemical and cellular selectivity the inhibitor series towards GSK3 beta. 5. does not inhibit EGFR signaling in HCC1954 cells. Table Sensitivity to Erlotinib Lung Cells CCLE. hematological malignacies cell lines.</p>
<div>Abstract<p><b>Purpose:</b> PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies.</p><p><b>Experimental Design:</b> Pan-PIM proven...
<div>Abstract<p><b>Purpose:</b> PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies.</p><p><b>Experimental Design:</b> Pan-PIM proven...
<p>PDF file - 650K, Figure S1. RSK N-terminal Kinase Directly Phosphorylates YB1 on Ser102. COS7 cells either (A) untransfected or (B) transiently expressing WT RSK2 T493M were placed under serum starvation conditions for 20 hrs, followed by 3 hour treatment with 1microM FMK-PA and subsequently stimulated 1ng/ml EGF 10 minutes. The levels of phosphorylated total proteins assessed in cell lysates using Western Blot. β-actin protein gel loading control. S2. LJH685 modulates BAD...
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