Professor
P_Pharmaceutical Chemistry
+1 415 514-4313
Michelle’s lab develops innovative approaches to screen for chemical tools and drug leads, using biophysical approaches like fragment-based drug discovery and biological approaches including high-content imaging with primary cells and organisms. Our goal is to demonstrate ‘druggability’ of new target classes and to use our compounds to discover new targets for drug discovery. Areas of interest include protein-protein interactions, allosteric and scaffolding sites in enzymes, and orphan and neglected diseases. Michelle is co-Director of the Small Molecule Discovery Center, a collaborative research and core lab that includes a high-throughput screening facility and medicinal chemistry (smdc.ucsf.edu).
Publications
Stabilization of Native Protein-Protein Interactions with Molecular Glues: A 14-3-3 Case Study.
Accounts of chemical research
Modulation of the 14-3-3σ/C-RAF "auto"inhibited complex by molecular glues.
bioRxiv : the preprint server for biology
Scaffold-hopping for molecular glues targeting the 14-3-3/ERα complex.
Nature communications
Opposing role of phagocytic receptors MERTK and AXL in Progranulin deficient FTD.
Communications biology
Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.
Proceedings of the National Academy of Sciences of the United States of America
Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus MPro inhibitors with potent in vivo efficacy.
Science advances
Synthetic Lethal Targeting of Cyclin Dependent Kinase-12-Deficient Prostate Cancer with PARP Inhibitors.
Clinical cancer research : an official journal of the American Association for Cancer Research
D13 caspase-6-cleaved tau, a new biomarker to complement Alzheimer’s disease diagnosis.
Alzheimer's & Dementia
Truncated tau accumulates before hyperphosphorylated tau and in relatively distinct neuronal subpopulations in entorhinal cortex and inferior temporal gyrus in Alzheimer’s disease patients.
Alzheimer's & Dementia
Deep phenotypic profiling of neuroactive drugs in larval zebrafish.
Nature communications
iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death.
Molecular and cellular neurosciences
14-3-3 Protein-Protein Interactions: From Mechanistic Understanding to Their Small-Molecule Stabilization.
Chembiochem : a European journal of chemical biology
Development of a NanoBRET assay for evaluation of 14-3-3σ molecular glues.
SLAS discovery : advancing life sciences R & D
Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.
American journal of human genetics
Molecular glues for protein-protein interactions: Progressing toward a new dream.
Cell chemical biology
Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement.
Analytical chemistry
An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis.
The Journal of clinical investigation
Synthetic autophagy receptor.
Autophagy
Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening.
RSC Chemical Biology
The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.
Nature structural & molecular biology
Autophagy Receptor-Inspired Antibody-Fusion Proteins for Targeted Intracellular Degradation.
Journal of the American Chemical Society
Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments.
Journal of the American Chemical Society
From tethered to freestanding stabilizers of 14-3-3 protein-protein interactions via fragment linking.
Angewandte Chemie (International ed. in English)
From tethered to freestanding stabilizers of 14-3-3 protein-protein interactions via fragment linking.
Angewandte Chemie
Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6.
Journal of medicinal chemistry
The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.
bioRxiv : the preprint server for biology
Abstract A018: A top-down proteomic assay to evaluate KRAS4B-compound engagement.
Molecular Cancer Research
IFNα primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization.
Cell chemical biology
Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.
Haematologica
Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.
Journal of the American Chemical Society
A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
ACS central science
Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERR? Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.
Journal of the American Chemical Society
Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for Carnitine Transporter Deficiency.
Proceedings of the National Academy of Sciences of the United States of America
LC3B Binds to the Autophagy Protease ATG4b with High Affinity Using a Bipartite Interface.
Biochemistry
Abstract B004: ATR-CHK1-WEE1 pathway is a critical dependency in the context of DNA damage and replicative stress in osteosarcoma.
Clinical Cancer Research
Cryo-EM structures reveal dramatic remodeling of the p97 hexamer by the multi-domain adapter UBXD1.
Acta Crystallographica Section A: Foundations and advances
Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions.
Journal of the American Chemical Society
Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: diagnostic and therapeutic implications.
Neuropathology and applied neurobiology
Phenotypic Screening Using High-Content Imaging to Identify Lysosomal pH Modulators in a Neuronal Cell Model.
ACS chemical neuroscience
Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine.
Cell chemical biology
In Vivo Dopamine Neuron Imaging-Based Small Molecule Screen Identifies Novel Neuroprotective Compounds and Targets.
Frontiers in pharmacology
Caspase-6-cleaved tau is relevant in Alzheimer's disease but not in 4-repeat tauopathies: Diagnostic and therapeutic implications.
Alzheimer's & Dementia
Caspase inhibition mitigates tau cleavage and neurotoxicity in iPSC-induced neurons with the V337M MAPT mutation.
Alzheimer's & Dementia
Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.
ACS medicinal chemistry letters
Real-Time Assessment of Mitochondrial Toxicity in HepG2 Cells Using the Seahorse Extracellular Flux Analyzer.
Current protocols
Reimagining dots and dashes: visualizing structure and function of organelles for high-content imaging analysis.
Cell chemical biology
An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.
Pathogens (Basel, Switzerland)
A multi-dimensional, time-lapse, high content screening platform applied to schistosomiasis drug discovery.
Communications biology
Caspase-6-mediated tau cleavage and pathology in Alzheimer’s disease and other tauopathies.
Alzheimer's & Dementia
Multiparametric High-Content Assays to Measure Cell Health and Oxidative Damage as a Model for Drug-Induced Liver Injury.
Current protocols in chemical biology
Fluorescence Anisotropy-Based Tethering for Discovery of Protein-Protein Interaction Stabilizers.
ACS chemical biology
Expression and Purification of Active Human Kinases Using Pichia pastoris as A General-Purpose Host.
Protein expression and purification
Author Correction: Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.
Nature immunology
High-Throughput Screening: today's biochemical and cell-based approaches.
Drug discovery today
Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex.
ACS chemical biology
Fragment-based Differential Targeting of PPI Stabilizer Interfaces.
Journal of medicinal chemistry
Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.
Nature immunology
Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans' Lifespan.
G3 (Bethesda, Md.)
Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.
Molecular neurodegeneration
A Cell-Based Renilla Luminescence Reporter Plasmid Assay for High-Throughput Screening to Identify Novel FDA-Approved Drug Inhibitors of HPV-16 Infection.
SLAS discovery : advancing life sciences R & D
Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases.
Nature chemical biology
TAU-MEDIATED CELL DEATH MECHANISMS IN MAPT V337M IPSC-DERIVED HUMAN NEURONS.
Alzheimer's & Dementia
Modulating protein-protein interaction networks in protein homeostasis.
Current opinion in chemical biology
Site-Directed Fragment-based Screening for the Discovery of Protein-Protein Interaction Stabilizers.
Journal of the American Chemical Society
Guidelines for DNA recombination and repair studies: Mechanistic assays of DNA repair processes.
Microbial cell (Graz, Austria)
Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.
Nature immunology
Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97.
ACS medicinal chemistry letters
A Genetic Interaction Map of Insulin Production Identifies Mfi as an Inhibitor of Mitochondrial Fission.
Endocrinology
Octopamine signaling in the metazoan pathogen Schistosoma mansoni: localization, small-molecule screening and opportunities for drug development.
Disease models & mechanisms
Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery.
Clinical and translational science
Abstract SY23-03: Development and mechanistic characterization of USP7 deubiquitinase inhibitors.
Cancer research
Small-Molecule Screening for Genetic Diseases.
Annual review of genomics and human genetics
EXTH-55. REPURPOSING THERAPEUTICS IN PATIENT-DERIVED GLIOMAS AND AN IDH1 MUTANT GLIOMA MODEL.
Neuro-Oncology
A Liquid Chromatography/Mass Spectrometry Method for Screening Disulfide Tethering Fragments.
SLAS discovery : advancing life sciences R & D
Chemical Biology as a Driver of Innovation in Cancer Research and Drug Discovery.
Cell chemical biology
Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans.
Neurobiology of aging
Applying Biophysical and Biochemical Methods to the Discovery of Allosteric Modulators of the AAA ATPase p97.
Applied Biophysics for Drug Discovery
Joining Forces: The Chemical Biology-Medicinal Chemistry Continuum.
Cell chemical biology
High-Throughput Screening To Identify Potent and Specific Inhibitors of Microbial Sulfate Reduction.
Environmental science & technology
A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site.
Organic & biomolecular chemistry
Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery.
Current topics in medicinal chemistry
Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen.
SLAS discovery : advancing life sciences R & D
p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.
ACS chemical biology
Challenges and solutions to developing an automated high-throughput/high-content screening platform for the ‘neglected’ schistosome parasite.
The FASEB Journal
2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition.
Science (New York, N.Y.)
Making FBDD Work in Academia.
Fragment-based Drug Discovery Lessons and Outlook
Interview with Michelle Arkin, PhD.
Assay and drug development technologies
Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway.
ACS medicinal chemistry letters
Covalent targeting of acquired cysteines in cancer.
Current opinion in chemical biology
Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97.
ACS medicinal chemistry letters
Tackling reproducibility in academic preclinical drug discovery.
Nature reviews. Drug discovery
Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease.
PLoS pathogens
Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery.
PLoS neglected tropical diseases
Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas' disease.
Bioorganic & medicinal chemistry letters
Altered cofactor regulation with disease-associated p97/VCP mutations.
Proceedings of the National Academy of Sciences of the United States of America
Tethering in RNA: an RNA-binding fragment discovery tool.
Molecules (Basel, Switzerland)
Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.
PLoS neglected tropical diseases
A Fragment-Based Ligand Screen Against Part of a Large Protein Machine: The ND1 Domains of the AAA+ ATPase p97/VCP.
Journal of biomolecular screening
Biophysical methods for identifying fragment-based inhibitors of protein-protein interactions.
Methods in molecular biology (Clifton, N.J.)
Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding.
The Biochemical journal
A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1.
Proceedings of the National Academy of Sciences of the United States of America
Lead identification to clinical candidate selection: drugs for Chagas disease.
Journal of biomolecular screening
Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.
Chemistry & biology
Screening for noise in gene expression identifies drug synergies.
Science (New York, N.Y.)
Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains.
Journal of molecular biology
UCSF Small Molecule Discovery Center: innovation, collaboration and chemical biology in the Bay Area.
Combinatorial chemistry & high throughput screening
Inhibiting caspase-6 activation and catalytic activity for neurodegenerative diseases.
Current topics in medicinal chemistry
Inside Cover: Tailoring Small Molecules for an Allosteric Site on Procaspase-6 (ChemMedChem 1/2014).
ChemMedChem
Probing structural adaptivity at PPI interfaces with small molecules.
Drug discovery today. Technologies
Bringing together the academic drug discovery community.
Nature reviews. Drug discovery
A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels.
ACS chemical biology
Abstract 5524: Library screen to rapidly determine activity against normal and mutant bone marrow progenitor cells.
Cancer research
Chemical-biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target.
Beilstein journal of organic chemistry
Protein–Protein Interactions – Inhibition.
Encyclopedia of Biophysics
Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis.
Proceedings of the National Academy of Sciences of the United States of America
Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51.
PLoS neglected tropical diseases
Analysis of high-throughput screening assays using cluster enrichment.
Statistics in medicine
Novel cruzain inhibitors for the treatment of Chagas' disease.
Chemical biology & drug design
A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target.
Nature medicine
Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.
ACS medicinal chemistry letters
Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis.
The Journal of biological chemistry
A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit.
PLoS neglected tropical diseases
Mining a cathepsin inhibitor library for new antiparasitic drug leads.
PLoS neglected tropical diseases
Screening technologies for unusual and challenging targets.
The FASEB Journal
A high-throughput turbidometric assay for screening inhibitors of Leishmania major protein disulfide isomerase.
Journal of biomolecular screening
An image-based assay for high throughput screening of Giardia lamblia.
Journal of microbiological methods
Small-molecule inhibitors of IL-2/IL-2R: lessons learned and applied.
Current topics in microbiology and immunology
Structure-activity relationship (SAR) of the a-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists.
Bioorganic & medicinal chemistry letters
Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.
Bioorganic & medicinal chemistry letters
Image-based high-throughput drug screening targeting the intracellular stage of Trypanosoma cruzi, the agent of Chagas' disease.
Antimicrobial agents and chemotherapy
Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II.
PloS one
Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
Journal of medicinal chemistry
Finding Small Molecule Ligands for Protein-Protein Interactions and Other “Undruggable” Targets.
Biophysical journal
Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases.
Bioorganic & medicinal chemistry letters
Two approaches to discovering and developing new drugs for Chagas disease.
Memorias do Instituto Oswaldo Cruz
The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions.
Current opinion in chemical biology
The marine sponge Diacarnus bismarckensis as a source of peroxiterpene inhibitors of Trypanosoma brucei, the causative agent of sleeping sickness.
Journal of natural products
SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples.
Cancer chemotherapy and pharmacology
HER-2-directed, small-molecule antagonists.
Current opinion in investigational drugs (London, England : 2000)
A diaminocyclohexyl analog of SNS-032 with improved permeability and bioavailability properties.
Bioorganic & medicinal chemistry letters
Protein-protein interactions and cancer: small molecules going in for the kill.
Current opinion in chemical biology
Identification of nonpeptidic small-molecule inhibitors of interleukin-2.
Bioorganic & medicinal chemistry letters
Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein-protein interactions.
Journal of medicinal chemistry
Small-molecule inhibitors of protein-protein interactions: progressing towards the dream.
Nature reviews. Drug discovery
Discovery and characterization of cooperative ligand binding in the adaptive region of interleukin-2.
Biochemistry
Discovery of a potent small molecule IL-2 inhibitor through fragment assembly.
Journal of the American Chemical Society
Binding of small molecules to an adaptive protein-protein interface.
Proceedings of the National Academy of Sciences of the United States of America
Drug discovery at signaling interfaces.
Ernst Schering Research Foundation workshop
A New Data Analysis Method to Determine Binding Constants of Small Molecules to Proteins Using Equilibrium Analytical Ultracentrifugation with Absorption Optics Volume 299, Number 1 (2001), pages 98–107.
Analytical biochemistry
A new data analysis method to determine binding constants of small molecules to proteins using equilibrium analytical ultracentrifugation with absorption optics.
Analytical biochemistry
In Vitro Mutagenesis.
Brenner\u0027s Encyclopedia of Genetics
In vitro Mutagenesis.
Encyclopedia of Genetics
Mutational Analysis.
Encyclopedia of Genetics
Probing the importance of second sphere residues in an esterolytic antibody by phage display.
Journal of molecular biology
First Observation of the Key Intermediate in the “Light-Switch” Mechanism of [Ru(phen) 2 dppz] 2+.
Journal of the American Chemical Society
Long-range oxidation of guanine by Ru(III) in duplex DNA.
Chemistry & biology
Oxidation of Guanine in DNA by Ru(phen) 2 (dppz) 3+ Using the Flash-Quench Technique.
Journal of the American Chemical Society
Rates of DNA-mediated electron transfer between metallointercalators.
Science (New York, N.Y.)
Luminescence Quenching in Supramolecular Systems: A Comparison of DNA- and SDS Micelle-Mediated Photoinduced Electron Transfer between Metal Complexes.
Journal of the American Chemical Society
DNA-mediated electron transfer.
Journal of Inorganic Biochemistry
Rates of electron transfer reactions between metallointercalators.
Journal of Inorganic Biochemistry
Tetrahydropterin Reactions of Dioxo-Molybdenum(6+) Complexes: Does Redox Occur?.
Journal of the American Chemical Society
Electron transfer between metallointercalators bound to DNA: Spectral identification of the transient intermediate.
Journal of the American Chemical Society
Fast photoinduced electron transfer through DNA intercalation.
Proceedings of the National Academy of Sciences of the United States of America
Long-range photoinduced electron transfer through a DNA helix.
Science (New York, N.Y.)
Evidence for photoelectron transfer through DNA intercalation.
Journal of Inorganic Biochemistry
Redox reactions of reduced pterins with copper and molybdenum complexes.
Journal of Inorganic Biochemistry