BET PROTACs Are More Broadly Effective Than BET Inhibitors. Dr. Kevin Coleman Arvinas, LLC New Haven, CT
|
|
- Edward O’Brien’
- 6 years ago
- Views:
Transcription
1 BET PROTACs Are More Broadly Effective Than BET Inhibitors Dr. Kevin Coleman Arvinas, LLC New Haven, CT 1
2 Disclosures I am an employee of and have an equity stake in Arvinas 2
3 Arvinas: The Protein Degradation Company Private company, founded July 2013 Founder: Dr. Craig Crews Licensed Technologies for Targeted Degradation of Proteins from Yale University 3
4 PROTACs Induce The Rapid Degradation Of Target Proteins Lys Ubiquiti Lys Degraded protei Target protein E3 ligase Target protein E3 Ligase PROTACs (Proteolysis-Targeting Chimera) are bifunctional chimeric molecules that recruit an E3 ligase to a target protein to induce its degradation Have successfully degraded proteins using ligands that bind to several E3 ligases, including cereblon, IAP2, MDM2, VHL PROTAC technology is robust: Have degraded >85% of proteins tested & potentially can degrade any unwanted protein Degradation of unwanted proteins is fast (hours), durable (days), and potent (pm) PROTAC technology is broadly applicable across target classes & therapeutic areas 4
5 BRD4 Is An Important Cancer Epigenetic Regulator BRD4 is a member of the Bromodomain and Extra-Terminal motif (BET) family of proteins BRD4 is an epigenetic reader of acetylated histones and regulates gene transcription through the recruitment of other proteins to super-enhancer regions BET inhibitors selectively disrupt transcription of a number of important cell- and lineage-specific genes including oncogenes, i.e., MYC H441 NSCLC Histone Valent and Zuber (2014) Cell Cycle 13:689 Shimamura et al. (2013) Clin Cancer Res 19:
6 ARV-825 Potently And Rapidly Degrades BRD4 In A Cereblon- And Proteasome-Dependent Manner ARV-825 ARV-825 ARV-825 BRD4 Actin Namalwa 0.1 mm ARV mm ARV-825 Namalwa Ramos ARV-825 is a potent degrader of all BET family members Lu et al. (2015) Chem. Biol 22:755 Namalwa 6
7 BET PROTACs Cause Prolonged BRD4 Degradation, MYC Suppression and Inhibition of Cell Proliferation Burkitt's Lymphoma Namalwa cells Compound Incubation 12 h Time after compound washout Compound Washout Immunoblot Cell Proliferation Lu et al. (2015) Chem. Biol 22:755 7
8 C a o v -3 -P R O T A C C a o v -3 -In h ib ito r C O V P R O T A C C O V In h ib ito r C O V P R O T A C C O V In h ib ito r C O V P R O T A C C O V In h ib ito r E S -2 -P R O T A C E S -2 -In h ib ito r K U R A M O C H I-P R O T A C K U R A M O C H I-In h ib ito r O V C A R -3 -P R O T A C O V C A R -3 -In h ib ito r O V P R O T A C O V In h ib ito r O V S A H O -P R O T A C O V S A H O -In h ib ito r R M U G -S -P R O T A C R M U G -S -In h ib ito r S N U P R O T A C S N U In h ib ito r T Y K -n u -P R O T A C T Y K -n u -In h ib ito r A P R O T A C A In h ib ito r C O V P R O T A C C O V In h ib ito r H O P R O T A C H O In h ib ito r K G N -P R O T A C K G N -In h ib ito r M C A S -P R O T A C M C A S -In h ib ito r O A W 4 2 -P R O T A C O A W 4 2 -In h ib ito r O V 7 -P R O T A C O V 7 -In h ib ito r O V IS E -P R O T A C O V IS E -In h ib ito r O V M A N A -P R O T A C O V M A N A -In h ib ito r O V T O K O -P R O T A C O V T O K O -In h ib ito r P A -1 -P R O T A C P A -1 -In h ib to r R K N -P R O T A C R K N -In h ib ito r R M G -I-P R O T A C R M G -I-In h ib ito r S K -O V -3 -P R O T A C S K -O V -3 -In h ib ito r T O V D -P R O T A C T O V D -In h ib ito r T O V -2 1 G -P R O T A C T O V -2 1 G -In h ib ito r A 2 0 -P R O T A C A 2 0 -In h ib ito r B C P -1 -P R O T A C B C P -1 -In h ib ito r D B -P R O T A C D B -In h ib ito r D O H H -2 -P R O T A C D O H H -2 -In h ib ito r F a ra g e -P R O T A C F a ra g e -In h ib ito r G R A N T A P R O T A C G R A N T A In h ib ito r H 9 -P R O T A C H 9 -In h ib ito r H H -P R O T A C H H -In h ib ito r H T -P R O T A C H T -In h ib ito r H u T P R O T A C H u T In h ib ito r H u T 7 8 -P R O T A C H u T 7 8 -In h ib ito r J e K o -1 -P R O T A C J e K o -1 -In h ib ito r J M 1 -P R O T A C J M 1 -In h ib ito r M a v e r-1 -P R O T A C M A V E R -1 -In h ib ito r M C P R O T A C M C In h ib ito r M in a m i-1 -P R O T A C M in a m i-1 -In h ib ito r M J -P R O T A C M J -In h ib ito r M L M A -P R O T A C M L M A -in h ib ito r N A L M -1 -P R O T A C N A M L -1 -in h ib ito r P fe iffe r-p R O T A C P fe iffe r-in h ib ito r O C I-L Y P R O T A C O C I-L Y In h ib ito r R E C -1 -P R O T A C R E C -1 -In h ib ito r R L -P R O T A C R L -In h ib ito r S R -P R O T A C S R -In h ib ito r S U -D H L -2 -P R O T A C S U -D H L -2 -In h ib ito r S U -D H L -4 -P R O T A C S U -D H L -4 -In h ib ito r S U -D H L -6 -P R O T A C S U -D H L -6 -In h ib ito r T o le d o -P R O T A C T o le d o -In h ib ito r T U R -P R O T A C T U R -In h ib ito r U P R O T A C U In h ib ito r W S U -D L C L 2 -P R O T A C W S U -D L C L 2 -In h ib ito r Z P R O T A C Z In h ib ito r C e ll P ro life ra tio n E C 5 0 (m M ) C e ll P ro life ra tio n E C 5 0 (m M ) Tumor Cell Lines Are Consistently More Sensitive To BET Degradation Than To BET Inhibition Log scale: mm ARCC-29 (BET PROTAC) OTX015 (BET Inhibitor) Ovarian Cancer Cell Lines Ovarian cancer cell lines are consistently more sensitive to BET protein degradation than they are to BET protein inhibition 54% of ovarian cancer cell lines are resistant to 10 mm OTX015 Breast and NSCLC cell lines are similarly more sensitive to BET PROTACs compared to BET inhibitors 200 nm 20 nm Lymphoma cell lines are more sensitive to BET inhibition compared to ovarian, breast, and NSCLC cell lines Nevertheless, lymphoma cell lines are largely more sensitive to BET protein degradation than they are to BET protein inhibition 8
9 BET PROTACs Have Superior Anti-Proliferative Activity in DLBCL Cells Compared to BETi s BRD4-binding moiety VHL-binding moiety ARV-771 (Active BET PROTAC) U2932 Raina et al. (2016) PNAS 113:7124 ARV-766 (Inactive diastereomer) RI-1 SU-DHL-6 SU-DHL-5 SU-DHL-10 9
10 BET PROTACs Have Superior Apoptotic Activity In DLBCL Cells Compared to BET Inhibitors Caspase 3/7 BET PROTACs have also been shown to have superior apoptotic activity than BET inhibitors in ovarian and prostate cancer cell lines 10
11 S U -D H L -6 T u m o r V o lu m e (m m 3 ) Intermittent Dosing Of The BET PROTAC ARCC-29 Causes Tumor Regression IV V e h ic le B IW P O V e h ic le Q D A R C C M P K b iw IV A R C C M P K b iw IV A R C C M P K b iw IV O T X M P K q d P O T r e a tm e n t D a y 27% TGI (3 MPK ARCC-29) 44% TGI (50 MPK OTX015) 68% TGI (6 MPK ARCC-29) Tumor regression (12 MPK ARCC-29) Once-weekly dosing of the BET PROTAC ARCC-29 also results in tumor stasis or regression in human prostate and ovarian cancer xenograft models 11
12 Plasma Conc. (nm) P l a s m a C o n c. ( n M ) R e l a t i v e C l e a v e d C a s p 3 L e v e l s R e l a t i v e B R D 4 L e v e l s The Bet PROTAC ARCC-29 Causes Rapid BRD4 Degradation And Caspase Activation SU-DHL-6 DLBCL Xenograft Model BRD4 cl.casp3 hmito BRD4 cl.casp3 hmito BRD4 cl.casp3 hmito BRD4 cl.casp3 hmito Veh 1h 3h Veh 6h 9h Veh 12h 15h Veh 18h 24h DC 90 Plasma Level P r e d i c t e d D C A R V P K / P D ARCC-29 P l a s m a C o n plasma c. ( n M ) conc.(nm) Relative R e l a t i v e B RBRD4 D 4 L e v elevels l s Relative cleaved caspase3 levels T i m e ( h ) Time Post-Dose (h) Relative BRD4 Levels Relative Cleaved Caspace3 Levels Free fraction of ARCC-29 stays above the predicted plasma concentration required to achieve 90% BRD4 knockdown for ~ 6 hours Maximal BRD4 knockdown occurs at 3 hours followed by robust caspase activation at 6 hours BRD4 protein levels return to untreated levels 24 h post-dose
13 BET PROTACs Are More Broadly Effective Than BET Inhibitors BET PROTACs cause robust BRD4 degradation and more prolonged c-myc suppression in vitro and have greater efficacy in vivo compared to BET inhibitors Tumor cell lines representing different tumor types are consistently more sensitive to BET protein degradation than BET protein inhibition BET PROTACs have superior anti-proliferative and apoptotic activity in DLBCL, prostate cancer, and ovarian cancer cells compared to BET inhibitors Intermittent dosing of BET PROTACs caused tumor regression or stasis in DLBCL, prostate cancer, and ovarian cancer xenograft models Arvinas BET PROTAC is planned to enter the clinic in 2H17 13
14 Acknowledgements Arvinas Biology Kanak Raina Jing Lu Martha Altieri Ann Marie Rossi Deborah Gordon Ryan Willard Jim Winkler Arvinas Chemistry Yimin Qian Xin Chen Jing Wang Hanqing Dong Andy Crew Yale University John Hines Craig Crews 14
The Institute of Cancer Research PHD STUDENTSHIP PROJECT PROPOSAL
The Institute of Cancer Research PHD STUDENTSHIP PROJECT PROPOSAL PROJECT DETAILS Project Title: Design and synthesis of libraries of bifunctional degraders for the discovery of new cancer targets SUPERVISORY
More informationCharacterizing degradation kinetics and cellular mechanisms of PROTAC compounds. Kristin M. Riching, Ph.D. Protein Degradation Therapeutics 2018
Characterizing degradation kinetics and cellular mechanisms of PROTAC compounds Kristin M. Riching, Ph.D. Protein Degradation Therapeutics 28 Understanding the Dynamics and Mechanisms of Protein Degradation
More informationCurrent Literature. Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
Current Literature Development of ighly Potent and Selective Steroidal Inhibitors and Degraders of CDK8 ACS Med. Chem. Lett. 2018, ASAP Rational Drug Development simplification Cortistatin A 16-30 steps;
More informationChemical aspects of the cell. Compounds that induce cell proliferation, differentiation and death
Chemical aspects of the cell Compounds that induce cell proliferation, differentiation and death Cell proliferation The cell cycle Chapter 17 Molecular Biology of the Cell 2 Cell cycle Chapter 17 Molecular
More informationInhibition of the AAA-ATPase p97 with the first in class inhibitor CB-5083 as a novel approach to treat cancer
Inhibition of the AAA-ATPase p97 with the first in class inhibitor CB-5083 as a novel approach to treat cancer Daniel Anderson, PhD Cleave Biosciences 1 Disclosure Information: AACR Annual meeting 2015
More informationChapter 15 Active Reading Guide Regulation of Gene Expression
Name: AP Biology Mr. Croft Chapter 15 Active Reading Guide Regulation of Gene Expression The overview for Chapter 15 introduces the idea that while all cells of an organism have all genes in the genome,
More informationDrosophila Apoptosis and the Regulation of the Caspase Cascade
Drosophila Apoptosis and the Regulation of the Caspase Cascade Kate Stafford March 18, 2005 Abstract The caspase cascade in Drosophila is controlled primarily by DIAP1 (Drosophila inhibitor of apoptosis),
More informationGene Control Mechanisms at Transcription and Translation Levels
Gene Control Mechanisms at Transcription and Translation Levels Dr. M. Vijayalakshmi School of Chemical and Biotechnology SASTRA University Joint Initiative of IITs and IISc Funded by MHRD Page 1 of 9
More informationActivation of STING with Synthetic Cyclic Dinucleotides and Synergy with Checkpoint Inhibition
Activation of STING with Synthetic Cyclic Dinucleotides and Synergy with Checkpoint Inhibition Sarah McWhirter, PhD Director, STING Program Aduro Biotech ICI Boston 2017 Presentation 1 Disclosures Sarah
More informationRegulation of gene expression. Premedical - Biology
Regulation of gene expression Premedical - Biology Regulation of gene expression in prokaryotic cell Operon units system of negative feedback positive and negative regulation in eukaryotic cell - at any
More informationControl of Gene Expression in Prokaryotes
Why? Control of Expression in Prokaryotes How do prokaryotes use operons to control gene expression? Houses usually have a light source in every room, but it would be a waste of energy to leave every light
More informationRegulation and signaling. Overview. Control of gene expression. Cells need to regulate the amounts of different proteins they express, depending on
Regulation and signaling Overview Cells need to regulate the amounts of different proteins they express, depending on cell development (skin vs liver cell) cell stage environmental conditions (food, temperature,
More informationA. Incorrect! The Cell Cycle contains 4 distinct phases: (1) G 1, (2) S Phase, (3) G 2 and (4) M Phase.
Molecular Cell Biology - Problem Drill 21: Cell Cycle and Cell Death Question No. 1 of 10 1. Which of the following statements about the cell cycle is correct? Question #1 (A) The Cell Cycle contains 3
More informationCELL CYCLE AND DIFFERENTIATION
CELL CYCLE AND DIFFERENTIATION Dewajani Purnomosari Department of Histology and Cell Biology Faculty of Medicine Universitas Gadjah Mada d.purnomosari@ugm.ac.id WHAT IS CELL CYCLE? 09/12/14 d.purnomosari@ugm.ac.id
More informationRas e la Cascata delle Piccole GTPasi
Roma 26-27 Giugno 2015 Multidisciplinarietà e Biologia Molecolare applicate alla pratica Clinica i Oncologica: un'opportunità ed un vantaggio per tuttitti Ras e la Cascata delle Piccole GTPasi Alvaro Leone
More informationTNFα 18hr. Control. CHX 18hr. TNFα+ CHX 18hr. TNFα: 18 18hr (KDa) PARP. Cleaved. Cleaved. Cleaved. Caspase3. Pellino3 shrna. Control shrna.
Survival ( %) a. TNFα 18hr b. Control sirna Pellino3 sirna TNFα: 18 18hr c. Control shrna Pellino3 shrna Caspase3 Actin Control d. Control shrna Pellino3 shrna *** 100 80 60 CHX 18hr 40 TNFα+ CHX 18hr
More informationSig2GRN: A Software Tool Linking Signaling Pathway with Gene Regulatory Network for Dynamic Simulation
Sig2GRN: A Software Tool Linking Signaling Pathway with Gene Regulatory Network for Dynamic Simulation Authors: Fan Zhang, Runsheng Liu and Jie Zheng Presented by: Fan Wu School of Computer Science and
More informationAnalysis of correlated mutations in Ras G-domain
www.bioinformation.net Volume 13(6) Hypothesis Analysis of correlated mutations in Ras G-domain Ekta Pathak * Bioinformatics Department, MMV, Banaras Hindu University. Ekta Pathak - E-mail: ektavpathak@gmail.com;
More informationThe Bcl3 Story : Collabora2ve Drug Discovery In Ac2on
The Bcl3 Story : Collabora2ve Drug Discovery In Ac2on Dr Andrew Westwell Drug Development & Model Systems Package Lead Dr Luke Piggo> Research Associate, WCRC Rachel Savery Trials Project Manager (Early
More informationTable of contents 1. Thermal denaturation assay with BRD4(BD2) incubated with the covalent inhibitors vs. their. non-covalent controls.
Supporting Information DESIGN AND CHARACTERIZATION OF NOVEL COVALENT BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS TARGETING A METHIONINE Olesya A. Kharenko a *, Reena G. Patel a, S. David Brown
More informationApoptosis in Mammalian Cells
Apoptosis in Mammalian Cells 7.16 2-10-05 Apoptosis is an important factor in many human diseases Cancer malignant cells evade death by suppressing apoptosis (too little apoptosis) Stroke damaged neurons
More informationThe Caspase System: a potential role in muscle proteolysis and meat quality? Tim Parr
The Caspase System: a potential role in muscle proteolysis and meat quality? Tim Parr Caroline Kemp, Ron Bardsley,, Peter Buttery Division of Nutritional Sciences, School of Biosciences, University of
More informationMechanisms of Cell Death
Mechanisms of Cell Death CELL DEATH AND FORMATION OF THE SEMICIRCULAR CANALS Carol M. Troy, MD PhD August 24, 2009 FROM: Fekete et al., Development 124: 2451 (1997) PHENOMENOLOGY OF CELL DEATH I. DEVELOPMENT
More informationZool 3200: Cell Biology Exam 5 4/27/15
Name: Trask Zool 3200: Cell Biology Exam 5 4/27/15 Answer each of the following short answer questions in the space provided, giving explanations when asked to do so. Circle the correct answer or answers
More informationInferring Transcriptional Regulatory Networks from Gene Expression Data II
Inferring Transcriptional Regulatory Networks from Gene Expression Data II Lectures 9 Oct 26, 2011 CSE 527 Computational Biology, Fall 2011 Instructor: Su-In Lee TA: Christopher Miles Monday & Wednesday
More informationTargeted Covalent Inhibitors: A Risk-Benefit Perspective
Targeted Covalent Inhibitors: A Risk-Benefit Perspective 2014 AAPS Annual Meeting and Exposition San Diego, CA, November 4, 2014 Thomas A. Baillie School of Pharmacy University of Washington Seattle, WA
More informationPlant Molecular and Cellular Biology Lecture 8: Mechanisms of Cell Cycle Control and DNA Synthesis Gary Peter
Plant Molecular and Cellular Biology Lecture 8: Mechanisms of Cell Cycle Control and DNA Synthesis Gary Peter 9/10/2008 1 Learning Objectives Explain why a cell cycle was selected for during evolution
More informationMechanisms. Cell Death. Carol M. Troy, MD PhD August 24, 2009 PHENOMENOLOGY OF CELL DEATH I. DEVELOPMENT 8/20/2009
Mechanisms of Cell Death Carol M. Troy, MD PhD August 24, 2009 PHENOMENOLOGY OF CELL DEATH I. DEVELOPMENT A. MORPHOGENESIS: SCULPTING/SHAPING STRUCTURES CREATION OF CAVITIES AND TUBES FUSION OF TISSUE
More informationLecture 10: Cyclins, cyclin kinases and cell division
Chem*3560 Lecture 10: Cyclins, cyclin kinases and cell division The eukaryotic cell cycle Actively growing mammalian cells divide roughly every 24 hours, and follow a precise sequence of events know as
More informationDrosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation
University of Massachusetts Medical School escholarship@umms Molecular, Cell and Cancer Biology Publications Molecular, Cell and Cancer Biology 9-1-2011 Drosophila IAP1-mediated ubiquitylation controls
More information(12) Patent Application Publication (10) Pub. No.: US 2017/ A1
US 20170037004A1 (19) United States (12) Patent Application Publication (10) Pub. o.: US 2017/0037004 A1 Crew et al. (43) Pub. Date: Feb. 9, 2017 (54) ALAIE-BASED MDULATRS F C07D 403/2 (2006.01) PRTELYSIS
More informationAdvanced Medicinal Chemistry SLIDES B
Advanced Medicinal Chemistry Filippo Minutolo CFU 3 (21 hours) SLIDES B Drug likeness - ADME two contradictory physico-chemical parameters to balance: 1) aqueous solubility 2) lipid membrane permeability
More informationSUPPLEMENTARY INFORMATION
DOI: 10.1038/ncb2362 Figure S1 CYLD and CASPASE 8 genes are co-regulated. Analysis of gene expression across 79 tissues was carried out as described previously [Ref: PMID: 18636086]. Briefly, microarray
More informationDynamic modeling and analysis of cancer cellular network motifs
SUPPLEMENTARY MATERIAL 1: Dynamic modeling and analysis of cancer cellular network motifs Mathieu Cloutier 1 and Edwin Wang 1,2* 1. Computational Chemistry and Bioinformatics Group, Biotechnology Research
More informationmrna proteins DNA predicts certain possible future health issues Limited info concerning evolving health; advanced measurement technologies
DA predicts certain possible future health issues mra Limited info concerning evolving health; advanced measurement technologies proteins Potentially comprehensive information concerning evolving health;
More informationFOXO1 transcription factor and its role in Tamoxifen- resistant breast cancer. Christina Warner. Department of Biochemistry and Molecular Biophysics
FOXO1 transcription factor and its role in Tamoxifen- resistant breast cancer Christina Warner Department of Biochemistry and Molecular Biophysics University of Arizona 85726 Abstract: 136 words Main Body:
More informationStructural basis of PROTAC cooperative recognition for selective protein degradation
SUPPLEMENTARY INFORMATION Structural basis of PROTAC cooperative recognition for selective protein degradation Morgan S. Gadd 1, Andrea Testa 1, Xavier Lucas 1, Kwok-Ho Chan, Wenzhang Chen, Douglas J.
More informationExploring the Contextual Sensitivity of Factors that Determine Cellto-Cell Variability in Receptor-Mediated Apoptosis
Exploring the Contextual Sensitivity of Factors that Determine Cellto-Cell Variability in Receptor-Mediated Apoptosis The Harvard community has made this article openly available. Please share how this
More informationControl of Gene Expression
Control of Gene Expression Mechanisms of Gene Control Gene Control in Eukaryotes Master Genes Gene Control In Prokaryotes Epigenetics Gene Expression The overall process by which information flows from
More informationMolecular Modeling Studies of RNA Polymerase II Inhibitors as Potential Anticancer Agents
INTERNATIONAL JOURNAL OF ADVANCES IN PHARMACY, BIOLOGY AND CHEMISTRY Molecular Modeling Studies of RNA Polymerase II Inhibitors as Potential Anticancer Agents Ankita Agarwal*, Sarvesh Paliwal, Ruchi Mishra
More informationPolymer-Caged Nanobins for Synergistic Cisplatin-Doxorubicin Combination Chemotherapy
S1 Polymer-Caged Nanobins for Synergistic Cisplatin-Doxorubicin Combination Chemotherapy Sang-Min Lee, Thomas V. O Halloran,* and SonBinh T. Nguyen* Department of Chemistry and the Center of Cancer Nanotechnology
More information+ regulation. ribosomes
central dogma + regulation rpl DNA tsx rrna trna mrna ribosomes tsl ribosomal proteins structural proteins transporters enzymes srna regulators RNAp DNAp tsx initiation control by transcription factors
More informationAlita Miller, PhD. Head of BioScience. April 24, 2017 ECCMID 2017 Vienna, Austria
ETX5 restoration of sulbactam activity against multidrug resistant Acinetobacter baumannii correlates with β-lactamase inhibition in vitro and in vivo Alita Miller, PhD Head of BioScience April, 07 ECCMID
More informationFrom transcriptome to epigenome, and back? Mattia Pelizzola Center for Genomic Science Istituto Italiano di Tecnologia (IIT), Milano
From transcriptome to epigenome, and back? Mattia Pelizzola Center for Genomic Science Istituto Italiano di Tecnologia (IIT), Milano m6a epitranscriptome m6a dynamics synthesis processing degradation m5c
More informationChapter 9 DNA recognition by eukaryotic transcription factors
Chapter 9 DNA recognition by eukaryotic transcription factors TRANSCRIPTION 101 Eukaryotic RNA polymerases RNA polymerase RNA polymerase I RNA polymerase II RNA polymerase III RNA polymerase IV Function
More informationCell Survival Curves (Chap. 3)
Cell Survival Curves (Chap. 3) Example of pedigress of EMT6 mouse cells Clone The in vitro cell survival curve Cell Survival Assay Dye exclusion assay: membrane integrity MTT assay: respiratory activity
More informationMonte Carlo study elucidates the type 1/type 2 choice in apoptotic death signaling in normal and cancer cells
Cells 2013, 2, 1-x manuscripts; doi:10.3390/cells20x000x OPEN ACCESS cells ISSN 2073-4409 www.mdpi.com/journal/cells Article Monte Carlo study elucidates the type 1/type 2 choice in apoptotic death signaling
More informationMeasuring TF-DNA interactions
Measuring TF-DNA interactions How is Biological Complexity Achieved? Mediated by Transcription Factors (TFs) 2 Regulation of Gene Expression by Transcription Factors TF trans-acting factors TF TF TF TF
More information16 The Cell Cycle. Chapter Outline The Eukaryotic Cell Cycle Regulators of Cell Cycle Progression The Events of M Phase Meiosis and Fertilization
The Cell Cycle 16 The Cell Cycle Chapter Outline The Eukaryotic Cell Cycle Regulators of Cell Cycle Progression The Events of M Phase Meiosis and Fertilization Introduction Self-reproduction is perhaps
More informationRegulation of Gene Expression
Chapter 18 Regulation of Gene Expression PowerPoint Lecture Presentations for Biology Eighth Edition Neil Campbell and Jane Reece Lectures by Chris Romero, updated by Erin Barley with contributions from
More informationREVIEW SESSION. Wednesday, September 15 5:30 PM SHANTZ 242 E
REVIEW SESSION Wednesday, September 15 5:30 PM SHANTZ 242 E Gene Regulation Gene Regulation Gene expression can be turned on, turned off, turned up or turned down! For example, as test time approaches,
More information13-3. Synthesis-Secretory pathway: Sort lumenal proteins, Secrete proteins, Sort membrane proteins
13-3. Synthesis-Secretory pathway: Sort lumenal proteins, Secrete proteins, Sort membrane proteins Molecular sorting: specific budding, vesicular transport, fusion 1. Why is this important? A. Form and
More informationProtein structure based approaches to inhibit Plasmodium DHODH for malaria
Protein structure based approaches to inhibit Plasmodium DHDH for malaria Peter Johnson University of Leeds, School of Chemistry email p.johnson@leeds.ac.uk Tools for protein structure based approaches
More informationDevelopment of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining
Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining Samer Haidar 1, Zouhair Bouaziz 2, Christelle Marminon 2, Tiomo Laitinen 3, Anti Poso
More informationRegulation of Gene Expression *
OpenStax-CNX module: m44534 1 Regulation of Gene Expression * OpenStax This work is produced by OpenStax-CNX and licensed under the Creative Commons Attribution License 4.0 By the end of this section,
More informationMarker-guided Targeted Therapy, PAPRi and Immune Checkpoint Therapy
Marker-guided Targeted Therapy, PAPRi and Immune Checkpoint Therapy Plenary Lecture 4 April 6, 3018 Global Breast Cancer Conference 2018 Incheon, Korea Mien-Chie Hung, PhD 洪明奇 Vice President for Basic
More informationClustering and Network
Clustering and Network Jing-Dong Jackie Han jdhan@picb.ac.cn http://www.picb.ac.cn/~jdhan Copy Right: Jing-Dong Jackie Han What is clustering? A way of grouping together data samples that are similar in
More informationLife Sciences 1a: Section 3B. The cell division cycle Objectives Understand the challenges to producing genetically identical daughter cells
Life Sciences 1a: Section 3B. The cell division cycle Objectives Understand the challenges to producing genetically identical daughter cells Understand how a simple biochemical oscillator can drive the
More informationIntroduction. Gene expression is the combined process of :
1 To know and explain: Regulation of Bacterial Gene Expression Constitutive ( house keeping) vs. Controllable genes OPERON structure and its role in gene regulation Regulation of Eukaryotic Gene Expression
More informationFRAGMENT SCREENING IN LEAD DISCOVERY BY WEAK AFFINITY CHROMATOGRAPHY (WAC )
FRAGMENT SCREENING IN LEAD DISCOVERY BY WEAK AFFINITY CHROMATOGRAPHY (WAC ) SARomics Biostructures AB & Red Glead Discovery AB Medicon Village, Lund, Sweden Fragment-based lead discovery The basic idea:
More informationRichik N. Ghosh, Linnette Grove, and Oleg Lapets ASSAY and Drug Development Technologies 2004, 2:
1 3/1/2005 A Quantitative Cell-Based High-Content Screening Assay for the Epidermal Growth Factor Receptor-Specific Activation of Mitogen-Activated Protein Kinase Richik N. Ghosh, Linnette Grove, and Oleg
More informationDesign Principles for Maximizing the Drug Delivery Efficiency and Therapeutic Index of ADCs
Design Principles for Maximizing the Drug Delivery Efficiency and Therapeutic Index of ADCs World ADC 217 San Diego Robert Lyon Sr. Director, Chemistry Themes of the presentation This represents the desired
More informationCell Death & Trophic Factors II. Steven McLoon Department of Neuroscience University of Minnesota
Cell Death & Trophic Factors II Steven McLoon Department of Neuroscience University of Minnesota 1 Remember? Neurotrophins are cell survival factors that neurons get from their target cells! There is a
More informationDispensing Processes Profoundly Impact Biological, Computational and Statistical Analyses
Dispensing Processes Profoundly Impact Biological, Computational and Statistical Analyses Sean Ekins 1, Joe Olechno 2 Antony J. Williams 3 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Labcyte Inc,
More informationFSC-W FSC-H CD4 CD62-L
Supplementary Fig. 1 a SSC-A FSC-A FSC-W FSC-H SSC-W SSC-H CD4 CD62-L b SSC-A FSC-A FSC-W FSC-A FSC-A 7-AAD FSC-A CD4 IL-9 CD4 c SSC-A FSC-A FSC-W FSC-H SSC-W SSC-H 7-AAD KI67 Annexin-V 7-AAD d I L -5
More informationData Quality Issues That Can Impact Drug Discovery
Data Quality Issues That Can Impact Drug Discovery Sean Ekins 1, Joe Olechno 2 Antony J. Williams 3 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Labcyte Inc, Sunnyvale, CA. 3 Royal Society of Chemistry,
More informationSociety for Biomolecular Screening 10th Annual Conference, Orlando, FL, September 11-15, 2004
Society for Biomolecular Screening 10th Annual Conference, Orlando, FL, September 11-15, 2004 Advanced Methods in Dose-Response Screening of Enzyme Inhibitors Petr uzmič, Ph.D. Bioin, Ltd. TOPICS: 1. Fitting
More informationApoptosis and Cancer. Carol M. Troy, MD, PhD October 26, 2016
Apoptosis and Cancer Carol M. Troy, MD, PhD October 26, 2016 PHENOMENOLOGY OF CELL DEATH -1 I. DEVELOPMENT A. MORPHOGENESIS: SCULPTING/SHAPING STRUCTURES FUSION OF TISSUE MASSES (PALATE/NEURAL TUBE) CREATION
More informationRegulation of Gene Expression
Chapter 18 Regulation of Gene Expression Edited by Shawn Lester PowerPoint Lecture Presentations for Biology Eighth Edition Neil Campbell and Jane Reece Lectures by Chris Romero, updated by Erin Barley
More informationAdvanced Topics in RNA and DNA. DNA Microarrays Aptamers
Quiz 1 Advanced Topics in RNA and DNA DNA Microarrays Aptamers 2 Quantifying mrna levels to asses protein expression 3 The DNA Microarray Experiment 4 Application of DNA Microarrays 5 Some applications
More informationSupporting Information
Supporting Information López et al. 10.1073/pnas.0810940106 1. Ivey DM, et al. (1993) Cloning and characterization of a putative Ca2 /H antiporter gene from Escherichia coli upon functional complementation
More information1. Ras-Interactors from the RASOMICS database
Transformation by ras oncogenes induces the deregulation of intracellular signalling cascades that are critical elements in cell growth control. Ras genes code for small GTPases that act as GDP/ GTP-regulated
More informationMicroplate-Based Measurements of Target Engagement in Live Cells With CETSA - a Reflection on Screen Results and Quantitative Interpretations
Microplate-Based Measurements of Target Engagement in Live Cells With CETSA - a Reflection on Screen Results and Quantitative Interpretations Thomas Lundbäck Karolinska Institutet ELRIG Drug Discovery
More informationZhike Zi. Constraint-Based Modeling and Kinetic Analysis of the Smad Dependent TGF-β Signaling Pathway
Constraint-Based Modeling and Kinetic Analysis of the Smad Dependent TGF-β Signaling Pathway Zhike Zi Computational Systems Biology Max-Planck Institute for Molecular Genetics Ihnestr. 73, 14195 Berlin,
More informationS1 Gene ontology (GO) analysis of the network alignment results
1 Supplementary Material for Effective comparative analysis of protein-protein interaction networks by measuring the steady-state network flow using a Markov model Hyundoo Jeong 1, Xiaoning Qian 1 and
More informationLipniacki 2004 Ground Truth
Abstract Lipniacki 2004 Ground Truth The two-feedback-loop regulatory module of nuclear factor kb (NF-kB) signaling pathway is modeled by means of ordinary differential equations. signaling pathway: https://en.wikipedia.org/wiki/signaling_pathway
More information16 CONTROL OF GENE EXPRESSION
16 CONTROL OF GENE EXPRESSION Chapter Outline 16.1 REGULATION OF GENE EXPRESSION IN PROKARYOTES The operon is the unit of transcription in prokaryotes The lac operon for lactose metabolism is transcribed
More informationThe EGF Signaling Pathway! Introduction! Introduction! Chem Lecture 10 Signal Transduction & Sensory Systems Part 3. EGF promotes cell growth
Chem 452 - Lecture 10 Signal Transduction & Sensory Systems Part 3 Question of the Day: Who is the son of Sevenless? Introduction! Signal transduction involves the changing of a cell s metabolism or gene
More informationHonors Biology Reading Guide Chapter 11
Honors Biology Reading Guide Chapter 11 v Promoter a specific nucleotide sequence in DNA located near the start of a gene that is the binding site for RNA polymerase and the place where transcription begins
More informationBioinformatics: Network Analysis
Bioinformatics: Network Analysis Kinetics of Gene Regulation COMP 572 (BIOS 572 / BIOE 564) - Fall 2013 Luay Nakhleh, Rice University 1 The simplest model of gene expression involves only two steps: the
More informationChemistry 1506: Allied Health Chemistry 2. Section 10: Enzymes. Biochemical Catalysts. Outline
Chemistry 1506 Dr. Hunter s Class Section 10 Notes - Page 1/14 Chemistry 1506: Allied Health Chemistry 2 Section 10: Enzymes Biochemical Catalysts. Outline SECTION 10.1 INTRODUCTION...2 SECTION SECTION
More informationRegulation of gene Expression in Prokaryotes & Eukaryotes
Regulation of gene Expression in Prokaryotes & Eukaryotes 1 The trp Operon Contains 5 genes coding for proteins (enzymes) required for the synthesis of the amino acid tryptophan. Also contains a promoter
More information7.013 Problem Set
7.013 Problem Set 5-2013 Question 1 During a summer hike you suddenly spot a huge grizzly bear. This emergency situation triggers a fight or flight response through a signaling pathway as shown below.
More informationMedicinal Chemistry and Chemical Biology
Medicinal Chemistry and Chemical Biology Activities Drug Discovery Imaging Chemical Biology Computational Chemistry Natural Product Synthesis Current Staff Mike Waring Professor of Medicinal Chemistry
More informationOverview. Database Overview Chart Databases. And now, a Few Words About Searching. How Database Content is Delivered
Databases Overview Database Overview Chart Databases ChemIndex / NCI Cancer and AIDS ChemACX The Merck Index Ashgate Drugs Traditional Chinese Medicines And now, a Few Words About Searching chemical structure
More informationQSAR Modeling of ErbB1 Inhibitors Using Genetic Algorithm-Based Regression
APPLICATION NOTE QSAR Modeling of ErbB1 Inhibitors Using Genetic Algorithm-Based Regression GAINING EFFICIENCY IN QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS ErbB1 kinase is the cell-surface receptor
More informationAnswer only in the space provided; short, concise answers are preferred and will be rewarded. Please be as neat as possible.
Molecular Cell Biology 5068 In class Exam 3 December 15, 2015 Exam Number: Please print your name: Instructions: Please write only on these pages, in the spaces allotted. Write your number on each page
More informationADAM FAMILY. ephrin A INTERAZIONE. Eph ADESIONE? PROTEOLISI ENDOCITOSI B A RISULTATO REPULSIONE. reverse. forward
ADAM FAMILY - a family of membrane-anchored metalloproteases that are known as A Disintegrin And Metalloprotease proteins and are key components in protein ectodomain shedding Eph A INTERAZIONE B ephrin
More informationExamination paper for Bi3016 Molecular Cell Biology
Department of Biology Examination paper for Bi3016 Molecular Cell Biology Academic contact during examination: Per Winge Phone: 99369359 Examination date: 20 th December 2017 Examination time (from-to):
More informationSimplifying Drug Discovery with JMP
Simplifying Drug Discovery with JMP John A. Wass, Ph.D. Quantum Cat Consultants, Lake Forest, IL Cele Abad-Zapatero, Ph.D. Adjunct Professor, Center for Pharmaceutical Biotechnology, University of Illinois
More informationBi 8 Lecture 11. Quantitative aspects of transcription factor binding and gene regulatory circuit design. Ellen Rothenberg 9 February 2016
Bi 8 Lecture 11 Quantitative aspects of transcription factor binding and gene regulatory circuit design Ellen Rothenberg 9 February 2016 Major take-home messages from λ phage system that apply to many
More informationChemotherapy in heterogeneous cultures of cancer cells with interconversion
Chemotherapy in heterogeneous cultures of cancer cells with interconversion Rui DILãO Institut des Hautes Études Scientifiques 35, route de Chartres 91440 Bures-sur-Yvette (France) Juin 2013 IHES/M/13/20
More informationVolume 12(2)
Open access www.bioinformation.net Volume 12(2) Hypothesis Insights from molecular modeling, docking and simulation of imidazole nucleus containing chalcones with EGFR kinase domain for improved binding
More informationNetwork Biology-part II
Network Biology-part II Jun Zhu, Ph. D. Professor of Genomics and Genetic Sciences Icahn Institute of Genomics and Multi-scale Biology The Tisch Cancer Institute Icahn Medical School at Mount Sinai New
More informationPing-Chiang Lyu. Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University.
Pharmacophore-based Drug design Ping-Chiang Lyu Institute of Bioinformatics and Structural Biology, Department of Life Science, National Tsing Hua University 96/08/07 Outline Part I: Analysis The analytical
More informationDocking with Water in the Binding Site using GOLD
Docking with Water in the Binding Site using GOLD Version 2.0 November 2017 GOLD v5.6 Table of Contents Docking with Water in the Binding Site... 2 Case Study... 3 Introduction... 3 Provided Input Files...
More informationEvidence for the Existence of Non-monotonic Dose-response: Does it or Doesn t it?
Evidence for the Existence of Non-monotonic Dose-response: Does it or Doesn t it? Scott M. Belcher, PhD University of Cincinnati Department of Pharmacology and Cell Biophysics Evidence for the Existence
More informationBE 150 Problem Set #2 Issued: 16 Jan 2013 Due: 23 Jan 2013
M. Elowitz and R. M. Murray Winter 2013 CALIFORNIA INSTITUTE OF TECHNOLOGY Biology and Biological Engineering (BBE) BE 150 Problem Set #2 Issued: 16 Jan 2013 Due: 23 Jan 2013 1. (Shaping pulses; based
More informationChem Lecture 10 Signal Transduction
Chem 452 - Lecture 10 Signal Transduction 111202 Here we look at the movement of a signal from the outside of a cell to its inside, where it elicits changes within the cell. These changes are usually mediated
More informationCells to Tissues. Peter Takizawa Department of Cell Biology
Cells to Tissues Peter Takizawa Department of Cell Biology From one cell to ensembles of cells. Multicellular organisms require individual cells to work together in functional groups. This means cells
More information