BPS Pharmacology 2016 Meeting - Albert Antolin
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This document discusses using computational methods to predict new targets of existing drugs, with a focus on polypharmacology of PARP inhibitors. Specifically: 1. Computational chemistry methods can predict new targets of drugs, identifying PIM1 kinase as a potential off-target of the PARP inhibitor PJ34. 2. Differential effects were observed between clinical PARP inhibitors rucaparib, olaparib, and veliparib in cancer cell lines and siRNA sensitivity, suggesting different off-target profiles. 3. Rucaparib inhibition of PIM1 kinase may have clinical implications, as PIM1 inhibition has been linked to increased liver toxicity, and ruc
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PERSONALIZED MEDICINE AND PHARMACOGENETICS
This document discusses personalized medicine and pharmacogenetics. It defines personalized medicine as tailoring medical treatment to an individual's characteristics. Pharmacogenetics is the study of how genetic differences influence variability in drug responses. The document outlines how genetic polymorphisms can impact drug metabolism and efficacy through variations in phase I and phase II drug metabolizing enzymes. It also categorizes different types of patients who may benefit from personalized medicine approaches based on factors like age, gender, medical conditions, and genetics.
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van Gool
This document describes the development of biomarkers to support targeted cancer therapies, using the case study of biomarkers for BRAF inhibitors in melanoma. Key points:
- The BRAFV600E mutation causes constitutive activation of the ERK pathway and is prevalent in melanoma, making it a promising drug target.
- siRNA and RAF inhibitor compounds were shown to inhibit the ERK pathway and cell proliferation in BRAF mutant cell lines but not wildtype lines, validating BRAF mutation as a predictive biomarker.
- Further optimization of RAF inhibitors focused on potency, selectivity against other kinases, and efficacy in mouse models to support clinical development.
- There remains a need to identify soluble protein biomarkers in blood
Soal dan Pembahasan Farmakogenomik dan Personalized Medicine
Materi farmakologi molekular farmakogenomik dan personalized medicine :
- penjelasan farmakogenomik, farmakogenetik, dan personalized medicine
- mekanisme kerja molekular warfarin dan clopidogrel terkait farmakogenomik
Plegable Biologia Molecular- Ana Maria Montufar
This document summarizes two scientific studies. The first study discovered a molecular switch in the cell nucleus that controls whether a cell survives or dies during autophagy. The second study found that noncoding 5S rRNA protects the p53 tumor suppressor gene by redirecting ribosomal proteins to inhibit the Hdm2 enzyme and increase p53 levels, inducing cell death in conditions of abnormal cell growth. Both studies represent potential new targets for developing improved medical treatments.
Safety and efficacy of aflibercept in combination with fluorouracil, leucovor...
Safety and efficacy of aflibercept in combination with fluorouracil, leucovor...Mary Ondinee Manalo Igot
This study evaluated the safety and efficacy of combining aflibercept with FOLFIRI chemotherapy (fluorouracil, leucovorin, irinotecan) in Asian patients with metastatic colorectal cancer who had progressed after prior oxaliplatin-based therapy. Nineteen patients received treatment with aflibercept and FOLFIRI. The combination showed a median progression-free survival of 4.1 months and median overall survival of 11.6 months. The majority of adverse events were grade 1-2 and included neutropenia, anemia, fatigue, and liver enzyme elevation. Grade 3 toxicities included neutropenia and neutropenic complications. All adverse events were managed with supportive care andOpportunities and challenges provided by crosstalk between signalling pathway...
This document summarizes opportunities and challenges in exploiting crosstalk between signaling pathways for cancer treatment. It discusses how inhibition of one pathway can activate a secondary survival pathway, conferring resistance. The review evaluates using genetic approaches to identify pathway crosstalk and develop combination therapies. It provides examples where targeting two interacting pathways showed stronger effects than single agents, including combinations of BRAF/EGFR inhibitors for BRAF mutant colon cancer and MEK/ERBB3 inhibitors for KRAS mutant cancers.
Pharmacogenomics- a step to personalized medicines
Pharmacogenomics aims to optimize drug therapy based on a patient's genotype to maximize efficacy and minimize adverse effects. It involves studying how genetic factors influence individual responses to drugs in terms of absorption, distribution, metabolism, and excretion. Genetic polymorphisms like SNPs that occur in over 1% of the population can impact a drug's effects. Pharmacogenomic testing identifies biomarkers related to drug metabolism and targets to determine effective treatments and dosages for patients. While it holds promise for improving drug development and personalized medicine, limitations include insufficient validation and high costs.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Pharmacology
Pharmacogenomics is the study of how an individual's genetic inheritance affects their response to drugs. It uses genomic tools in traditional pharmacology to enable predictive and personalized medication. The first observations of genetic variations affecting drug response date back to the 1950s. Approximately 106,000 deaths and 2.2 million serious adverse drug reactions occur each year due to the fact that "one size does not fit all" when it comes to medications. Pharmacogenomic technologies like genotyping and protein sequencing are used today to study how variations in genes like CYP450 and TPMT that encode drug-metabolizing enzymes can impact drug efficacy and safety.
Molecular Profiling of Cholangiocarcinoma - Milind Javle, MD
From the 2014 Cholangiocarcinoma Foundation's Stakeholders Meeting. February 27-28, 2014 at the Huntsman Cancer Institute, University of Utah
Caffeine against cancer and novel therapies for solid tumors
2 recent news that talk about the DNA replication and reparation, the caffeine as a skin cancer preventive agent and the use of PARP inhibitors instead of topotecan in chemotherapy.
Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD
Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Joseph Levy MedicReS World Congress 2013 - 2
This document discusses challenges in designing pharmacogenomics clinical trials. It provides an overview of pharmacogenomics and different types of pharmacogenomics studies. It then discusses three common clinical trial designs - subgroups analysis design, enrichment design, and genotype-guided design - and their advantages and disadvantages. Key challenges in pharmacogenomics clinical trials include small sample sizes for subgroups, possible confounding and selection biases, and statistical power issues. Prospective clinical trials are needed to validate predictive biomarkers and assess clinical utility of genotype-guided treatments.
Pharmacogenetics and Pharmacogenomics
Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.
Biomarkers & Clinical Research
4th International Conference on Biomarkers & Clinical Research, will be organized around the theme "Impact of Biomarker Developments in Health Diagnostics and Clinical Research."
Similar to BPS Pharmacology 2016 Meeting - Albert Antolin (20)
Executive Summary_Smart Analyst_PARP Inhibitors (Repaired)
Executive Summary_Smart Analyst_PARP Inhibitors (Repaired)
MDC Connects: Use of pre-clinical models to deliver proof of concept efficacy
MDC Connects: Use of pre-clinical models to deliver proof of concept efficacy
Clinical Utility of Pharmacogenetic Testing in Compounding Pharmacy
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2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van Gool
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van Gool
Soal dan Pembahasan Farmakogenomik dan Personalized Medicine
Soal dan Pembahasan Farmakogenomik dan Personalized Medicine
Safety and efficacy of aflibercept in combination with fluorouracil, leucovor...
Safety and efficacy of aflibercept in combination with fluorouracil, leucovor...
Opportunities and challenges provided by crosstalk between signalling pathway...
Opportunities and challenges provided by crosstalk between signalling pathway...
Pharmacogenomics- a step to personalized medicines
Pharmacogenomics- a step to personalized medicines
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...
Molecular Profiling of Cholangiocarcinoma - Milind Javle, MD
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Caffeine against cancer and novel therapies for solid tumors
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Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD
Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD
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Mending Clothing to Support Sustainable Fashion_CIMaR 2024.pdf
Ozturkcan, S., Berndt, A., & Angelakis, A. (2024). Mending clothing to support sustainable fashion. Presented at the 31st Annual Conference by the Consortium for International Marketing Research (CIMaR), 10-13 Jun 2024, University of Gävle, Sweden.
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.JAMES WEBB STUDY THE MASSIVE BLACK HOLE SEEDS
The pathway(s) to seeding the massive black holes (MBHs) that exist at the heart of galaxies in the present and distant Universe remains an unsolved problem. Here we categorise, describe and quantitatively discuss the formation pathways of both light and heavy seeds. We emphasise that the most recent computational models suggest that rather than a bimodal-like mass spectrum between light and heavy seeds with light at one end and heavy at the other that instead a continuum exists. Light seeds being more ubiquitous and the heavier seeds becoming less and less abundant due the rarer environmental conditions required for their formation. We therefore examine the different mechanisms that give rise to different seed mass spectrums. We show how and why the mechanisms that produce the heaviest seeds are also among the rarest events in the Universe and are hence extremely unlikely to be the seeds for the vast majority of the MBH population. We quantify, within the limits of the current large uncertainties in the seeding processes, the expected number densities of the seed mass spectrum. We argue that light seeds must be at least 103 to 105 times more numerous than heavy seeds to explain the MBH population as a whole. Based on our current understanding of the seed population this makes heavy seeds (Mseed > 103 M⊙) a significantly more likely pathway given that heavy seeds have an abundance pattern than is close to and likely in excess of 10−4 compared to light seeds. Finally, we examine the current state-of-the-art in numerical calculations and recent observations and plot a path forward for near-future advances in both domains.
The binding of cosmological structures by massless topological defects
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Discovery of An Apparent Red, High-Velocity Type Ia Supernova at 𝐳 = 2.9 wi...
We present the JWST discovery of SN 2023adsy, a transient object located in a host galaxy JADES-GS
+
53.13485
−
27.82088
with a host spectroscopic redshift of
2.903
±
0.007
. The transient was identified in deep James Webb Space Telescope (JWST)/NIRCam imaging from the JWST Advanced Deep Extragalactic Survey (JADES) program. Photometric and spectroscopic followup with NIRCam and NIRSpec, respectively, confirm the redshift and yield UV-NIR light-curve, NIR color, and spectroscopic information all consistent with a Type Ia classification. Despite its classification as a likely SN Ia, SN 2023adsy is both fairly red (
�
(
�
−
�
)
∼
0.9
) despite a host galaxy with low-extinction and has a high Ca II velocity (
19
,
000
±
2
,
000
km/s) compared to the general population of SNe Ia. While these characteristics are consistent with some Ca-rich SNe Ia, particularly SN 2016hnk, SN 2023adsy is intrinsically brighter than the low-
�
Ca-rich population. Although such an object is too red for any low-
�
cosmological sample, we apply a fiducial standardization approach to SN 2023adsy and find that the SN 2023adsy luminosity distance measurement is in excellent agreement (
≲
1
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) with
Λ
CDM. Therefore unlike low-
�
Ca-rich SNe Ia, SN 2023adsy is standardizable and gives no indication that SN Ia standardized luminosities change significantly with redshift. A larger sample of distant SNe Ia is required to determine if SN Ia population characteristics at high-
�
truly diverge from their low-
�
counterparts, and to confirm that standardized luminosities nevertheless remain constant with redshift.
Anti-Universe And Emergent Gravity and the Dark Universe
Recent theoretical progress indicates that spacetime and gravity emerge together from the entanglement structure of an underlying microscopic theory. These ideas are best understood in Anti-de Sitter space, where they rely on the area law for entanglement entropy. The extension to de Sitter space requires taking into account the entropy and temperature associated with the cosmological horizon. Using insights from string theory, black hole physics and quantum information theory we argue that the positive dark energy leads to a thermal volume law contribution to the entropy that overtakes the area law precisely at the cosmological horizon. Due to the competition between area and volume law entanglement the microscopic de Sitter states do not thermalise at sub-Hubble scales: they exhibit memory effects in the form of an entropy displacement caused by matter. The emergent laws of gravity contain an additional ‘dark’ gravitational force describing the ‘elastic’ response due to the entropy displacement. We derive an estimate of the strength of this extra force in terms of the baryonic mass, Newton’s constant and the Hubble acceleration scale a0 = cH0, and provide evidence for the fact that this additional ‘dark gravity force’ explains the observed phenomena in galaxies and clusters currently attributed to dark matter.
Alternate Wetting and Drying - Climate Smart Agriculture
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PPT on Alternate Wetting and Drying presented at the three-day 'Training and Validation Workshop on Modules of Climate Smart Agriculture (CSA) Technologies in South Asia' workshop on April 22, 2024. Applied Science: Thermodynamics, Laws & Methodology.pdf
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
11.1 Role of physical biological in deterioration of grains.pdf
Storagedeteriorationisanyformoflossinquantityandqualityofbio-materials.
Themajorcausesofdeteriorationinstorage
•Physical
•Biological
•Mechanical
•Chemical
Storageonlypreservesquality.Itneverimprovesquality.
Itisadvisabletostartstoragewithqualityfoodproduct.Productwithinitialpoorqualityquicklydepreciates
Methods of grain storage Structures in India.pdf
•Post-harvestlossesaccountforabout10%oftotalfoodgrainsduetounscientificstorage,insects,rodents,micro-organismsetc.,
•Totalfoodgrainproductioninindiais311milliontonnesandstorageis145mt.InIndia,annualstoragelosseshavebeenestimated14mtworthofRs.7,000croreinwhichinsectsaloneaccountfornearlyRs.1,300crores.
•InIndiaoutofthetotalproduction,about30%ismarketablesurplus
•Remaining70%isretainedandstoredbyfarmersforconsumption,seed,feed.Hence,growerneedstoragefacilitytoholdaportionofproducetosellwhenthemarketingpriceisfavourable
•TradersandCo-operativesatmarketcentresneedstoragestructurestoholdgrainswhenthetransportfacilityisinadequate
Farming systems analysis: what have we learnt?.pptx
Presentation given at the official farewell of Prof Ken Gillet at Wageningen on 13 June 2024
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...
By harnessing the power of High Flux Vacuum Membrane Distillation, Travis Hills from MN envisions a future where clean and safe drinking water is accessible to all, regardless of geographical location or economic status.
The cost of acquiring information by natural selection
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
CLASS 12th CHEMISTRY SOLID STATE ppt (Animated)
Description:
Dive into the fascinating realm of solid-state physics with our meticulously crafted online PowerPoint presentation. This immersive educational resource offers a comprehensive exploration of the fundamental concepts, theories, and applications within the realm of solid-state physics.
From crystalline structures to semiconductor devices, this presentation delves into the intricate principles governing the behavior of solids, providing clear explanations and illustrative examples to enhance understanding. Whether you're a student delving into the subject for the first time or a seasoned researcher seeking to deepen your knowledge, our presentation offers valuable insights and in-depth analyses to cater to various levels of expertise.
Key topics covered include:
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Band Theory: Explore the electronic band structure of solids and understand how it influences their conductive properties.
Semiconductor Physics: Delve into the behavior of semiconductors, including doping, carrier transport, and device applications.
Magnetic Properties: Investigate the magnetic behavior of solids, including ferromagnetism, antiferromagnetism, and ferrimagnetism.
Optical Properties: Examine the interaction of light with solids, including absorption, reflection, and transmission phenomena.
With visually engaging slides, informative content, and interactive elements, our online PowerPoint presentation serves as a valuable resource for students, educators, and enthusiasts alike, facilitating a deeper understanding of the captivating world of solid-state physics. Explore the intricacies of solid-state materials and unlock the secrets behind their remarkable properties with our comprehensive presentation.
Summary Of transcription and Translation.pdf
Hello Everyone Here We are Sharing You with The process of protien Synthesis in very short points you will be Able to understand It Very well
HUMAN EYE By-R.M Class 10 phy best digital notes.pdf
Class 10 human eye notes physics
Handwritten best quality
fermented food science of sauerkraut.pptx
This ppt contains the production of a fermented food name - sauerkraut
快速办理(UAM毕业证书)马德里自治大学毕业证学位证一模一样
学校原件一模一样【微信：741003700 】《(UAM毕业证书)马德里自治大学毕业证学位证》【微信：741003700 】学位证，留信认证（真实可查，永久存档）原件一模一样纸张工艺/offer、雅思、外壳等材料/诚信可靠,可直接看成品样本，帮您解决无法毕业带来的各种难题！外壳，原版制作，诚信可靠，可直接看成品样本。行业标杆！精益求精，诚心合作，真诚制作！多年品质 ,按需精细制作，24小时接单,全套进口原装设备。十五年致力于帮助留学生解决难题，包您满意。
本公司拥有海外各大学样板无数，能完美还原。
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◇在校期间，因各种原因未能顺利毕业……拿不到官方毕业证【q/微741003700】
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3:国家专业人才认证中心颁发入库证书
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6:个人职称评审加20分
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GBSN - Biochemistry (Unit 6) Chemistry of Proteins
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ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...
The binding of cosmological structures by massless topological defects
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Discovery of An Apparent Red, High-Velocity Type Ia Supernova at 𝐳 = 2.9 wi...
Discovery of An Apparent Red, High-Velocity Type Ia Supernova at 𝐳 = 2.9 wi...
Anti-Universe And Emergent Gravity and the Dark Universe
Anti-Universe And Emergent Gravity and the Dark Universe
Alternate Wetting and Drying - Climate Smart Agriculture
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Applied Science: Thermodynamics, Laws & Methodology.pdf
Applied Science: Thermodynamics, Laws & Methodology.pdf
11.1 Role of physical biological in deterioration of grains.pdf
11.1 Role of physical biological in deterioration of grains.pdf
Farming systems analysis: what have we learnt?.pptx
Farming systems analysis: what have we learnt?.pptx
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...
The cost of acquiring information by natural selection
The cost of acquiring information by natural selection
HUMAN EYE By-R.M Class 10 phy best digital notes.pdf
HUMAN EYE By-R.M Class 10 phy best digital notes.pdf
BPS Pharmacology 2016 Meeting - Albert Antolin
- 1. in partnership with Identification of differential kinase off-targets among PARP inhibitors: new opportunities for precision oncology? Albert A. Antolin, Jordi Mestres, Paul Workman & Bissan Al-Lazikani Marie Curie Tecniospring PostDoctoral Fellow Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK & GRIB, IMIM Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, Spain.
- 2. Polypharmacology and the limits of reductionism It is increasingly accepted that drugs tend to bind to more than one target, a behavior referred to as polypharmacology. Ehrlich, 1901 Vogt & Mestres, 2010 Tym JE, et al. 2016 Only 15% of drugs are currently known to interact with just one protein Jalencas & Mestres, 2013 2 How does polypharmacology influence clinical eficacy? Systems ApproachReductionism
- 3. Towards personalized and precision oncology 3 Antolin AA, et al. Curr Pharm Des, in press. Predictive Biomarker • Biomarkers of response • Polypharmacology can be exploited to extend the uses of cancer drugs without unacceptable toxicity.
- 4. • Drug-target network of imatinib with polypharmacology biomarkers • 10-fold selectivity cutoff Current exploitation of drug polypharmacology 4 Antolin AA, et al. Curr Pharm Des, in press.
- 5. • Identify new targets of known drugs • Link them to predictive biomarkers using systems pharmacology data to identify new patient populations responding to these drugs through polypharmacology. Objective 5
- 6. 1. Using chemical similarity we can predict new targets of compounds: 2. PARP chemical probe PJ34 as an example: Predicting polypharmacology 6 Antolin AA, et al. ACS Chem Bio. 2012 PJ34 PARP1/2 (20nM) PIM1 kinase predicted CHEMBL572783 PIM1/2 (8 and 3 nM) superposition IC50 = 3.7 µM IC50 = 16 µM In vitro validation (isolated protein)
- 7. • At the cellular level: 1. Differential cancer cell line profile (Sanger) 2. Differential siRNA sensitivity 3. Differential anti-proliferative activities, cell cycle arrest and DNA damage 4. Differential PARP trapping 5. … Differential effects between clinical PARP inhibitors 7 Rucaparib Olaparib Veliparib Chuang HC, et al. Breast Cancer Res Treat. 2012
- 8. 1. Does PJ34 polypharmacology translate into PARP clinical candidates? PARP inhibitors inhibit kinases off-target 8 Antolin AA & Mestres J. Oncotarget. 2014 PIM1 IC50 = 1.2 µM Rucaparib (PARP1 IC50 = 5 nM)
- 9. • Pim kinases phosphorylate STAT3 Differential effects between PARP inhibitors 9 Rucaparib Olaparib Veliparib Chuang HC, et al. Breast Cancer Res Treat. 2012
- 10. 1. Rucaparib Cmax: 2-9 µM > PIM1 IC50 = 1,2 µM 2. Free drug concentration? Tumor retention? 3. Different side-effect profile among PARP inhibitors PIM kinase inhibitor AZD1208 produces increased transaminases. Does PIM1 off-target inhibition have clinical implications? 10
- 11. Harnessing polypharmacology in precision oncology 11 • Sir Henry Wellcome Postdoctoral Fellowship Drug (Olaparib) Primary Target (PARPs) Off-target (PIM1) Predictive Biomarker DNA
- 12. Summary 12 • Many new targets of drugs remain to be identified and computational chemistry methods are becoming a cost-effective approach to off-target identification. • Precision oncology offers a means to better exploit this polypharmacology through predictive biomarkers • Different disciplines should work together to enable the clinical application of systems pharmacology and the maximum exploitation of currently available drugs to maximize patient benefit.
- 13. in partnership with Thank you! Bissan Al-Lazikani Paul Workman Jordi Mestres CBCG Team Elizabeth Coker Costas Mitsopoulos Joe Tym Carmen Rodriguez-Gonzalvez Veronica Garcia – Perez Sheng Yu Catherine Fletcher Sebastian Poetsrl James Campbell Patrizio di Micco STMP Team Paul Clarke Chi Zhang Alexia Hervieu Systems Pharmacology Group Xavier Jalencas Joaquim Olives Viktoria Szabo Nikita Remez (CT) David Vidal (CT) Ricard Garcia-Serna (CT) MariCarmen Carrascosa (CT) Johann de Bono DDU Team Udai Banerji Stan Kaye
- 15. Predicting new drug targets 15 drugs of interest 5658 targets Vidal et al. Methods Mol Biol 672 (2011) 489