PD0332991 is a highly selective CDK4/6 inhibitor that was optimized through a structure-activity relationship study. It demonstrated potent inhibition of CDK4 with little activity against other kinases. PD0332991 showed good oral bioavailability and pharmacokinetics in rats. In vivo studies found it inhibited tumor growth in breast and colon cancer models at well-tolerated doses through daily oral administration, establishing its potential as a cancer treatment.
Target Validation Academy Of Medical Sciences 1 Dec 2006Mike Romanos
An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences
genotoxicity,guidelines and history of genotoxicity,importance of genotoxicity,causactive agents of genotoxicity,invitro,invivo methods of genotoxicity studies.
Target Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
Target Validation Academy Of Medical Sciences 1 Dec 2006Mike Romanos
An overview of the issues and approaches in selecting the best targets for drug discovery and validating them. Given at the Drug Discovery Forum held at the Royal Society, London and organised by the Academy of Medical Sciences
genotoxicity,guidelines and history of genotoxicity,importance of genotoxicity,causactive agents of genotoxicity,invitro,invivo methods of genotoxicity studies.
Target Validation
Introduction,Drug discovery, Target identification and validation, Target validation and techniques
By
Ms. B. Mary Vishali
Department of Pharmacology
ACRI is a leading clinical research training institute in Bangalore.
ACRI creates a value add for every degree. Our PGDCRCDM course is approved by the Mysore University. Graduates and Post Graduates and even PhDs have trained with us and got enviable positions in the Clinical Research Industry. ACRI supplements University training with Industry based training, coupled with hands-on internships and projects based on real case studies. The ACRI brand gives the individual the confidence and expertise to join the ever-growing workforce both in the country and abroad.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices
Speaker: Jack Jiang, VP Medicinal and Analytical Chemistry, Ricerca BioSciences
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van GoolAlain van Gool
Tutorial lecture explaining real case stories of oncology drug development, passing on lessons learned from my pharma days to an audience of research professionals.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
Introduction to Applications of Proteomics Science,
Proteomics- Techniques, Applications of proteomics
Presented by
A. Harsha Vardhan Naidu
Department of Pharmacology
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Translational Genomics and Prostate Cancer: Meet the NGS Experts Series Part 2QIAGEN
Advanced prostate cancer is highly heterogeneous but this inter-patient heterogeneity has until recently not been understood. We have through an international research effort dissected the molecular landscape of advanced castration resistant prostate, elucidating key molecular targets in this group of diseases. We have also shown that PARP inhibitors have antitumor activity against a significant proportion of these cancers, mainly in men whose cancers harbor DNA repair defects.
ACRI is a leading clinical research training institute in Bangalore.
ACRI creates a value add for every degree. Our PGDCRCDM course is approved by the Mysore University. Graduates and Post Graduates and even PhDs have trained with us and got enviable positions in the Clinical Research Industry. ACRI supplements University training with Industry based training, coupled with hands-on internships and projects based on real case studies. The ACRI brand gives the individual the confidence and expertise to join the ever-growing workforce both in the country and abroad.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices
Speaker: Jack Jiang, VP Medicinal and Analytical Chemistry, Ricerca BioSciences
2015 11-26 ODDP2015 Course Oncology Drug Development, Amsterdam, Alain van GoolAlain van Gool
Tutorial lecture explaining real case stories of oncology drug development, passing on lessons learned from my pharma days to an audience of research professionals.
Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
Introduction to Applications of Proteomics Science,
Proteomics- Techniques, Applications of proteomics
Presented by
A. Harsha Vardhan Naidu
Department of Pharmacology
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Translational Genomics and Prostate Cancer: Meet the NGS Experts Series Part 2QIAGEN
Advanced prostate cancer is highly heterogeneous but this inter-patient heterogeneity has until recently not been understood. We have through an international research effort dissected the molecular landscape of advanced castration resistant prostate, elucidating key molecular targets in this group of diseases. We have also shown that PARP inhibitors have antitumor activity against a significant proportion of these cancers, mainly in men whose cancers harbor DNA repair defects.
Bioanalytical support plays a vital role during the lead optimization stages. The major goal of the bioanalysis is to assess the over-all ADME characteristics of the NCEs and biologics. Bioanalytical tools can play a significant role and impact the progress in drug discovery and development. Dramatic increases in investments in new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and ADC, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME and PK properties.https://www.medicilon.com/blog/featured-stories/dmpk-bioanalysis/
Carbon-14 labelled ADCs and Peptides by Sean L Kitsonseankitson
Abstract
Guided by a specific monoclonal antibody (mAb), antibody drug conjugates or ADC are a new, emerging, class of drugs able to deliver a drug payload directly to an intended target. This approach has recently been boosted by the U.S. Food and Drug Administration approval of brentuximab vedotin (Adcetris®; Seattle Genetics) to treat Hodgkin’s lymphoma and ado-trastuzumab emtansine (Kadcyla®; Genentech) for metastatic breast cancer. These new biotherapeutic drugs will bring many regulatory issues to the forefront regarding the ADME (Absorption, Distribution, Metabolism and Excretion) profile of each ADC. In this article, the authors discuss this and other important aspects of antibody-drug conjugates.
Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.
In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.
Discovery of Small Molecules As Potential Therapeutics For NAFLD and HCCBAU C...Trustlife
NAFLD (Non-Alcoholic Fatty Liver Disease) is a prevalent
liver disease caused by fat buildup in the liver, progression
advances to severe conditions like Fibrosis, cirrhosis, and
eventually liver cancer (HCC).
NAFLD, affecting approximately 25% of the global
population, is a highly prevalent liver disease linked to
obesity, diabetes, and metabolic syndrome, and is a
significant risk factor for the development of HCC, the fourth
leading cause of cancer-related deaths worldwide.
The study aims to provide insights into the mechanisms
underlying the development of HCC in patients with NAFLD,
which can help in early detection, prevention, and treatment
strategies.
As of now, there is no FDA-approved drug reported to treat
NAFLD.
Dr. Ananda Kumar Kondepati, M.D. and
Dr. Shalini D. Pasumarthi, M.D.
Canada, 2015
Clinical Research Program Supervisor:
Pr. Peivand Pirouzi, Ph.D., M.B.A., C.C.P.E.
This presentation includes details about ADEPT(Antibody Directed Enzyme prodrug Therapy), various challenges that one should meet to design an ADEPT and various enzymes and prodrugs that are reported and also the data of clinical studies.
Comprehensive Investigation of the Utilization of SFC/ESI Positive Mode MS fo...Waters Corporation
Bioanalysis and drug metabolism studies are critical parts of the drug development process. The aim of these studies is to identify and quantify drugs and their associated metabolites in biofluids such as plasma and urine. Typically reversed-phase chromatography coupled with mass spectrometry is often the analytical technique of choice utilized in the analyses due to the specificity and sensitivity of the technique. However, due to the complexity of the biofluid samples accurate and precise measurements can become challenging due to poor chromatographic peak shape, insufficient chromatographic resolution from matrix components and incompatible sample compositions.
Recent advancements in the field of super critical fluid chromatography (SFC) have lead to the development of sub 2 micron chromatographic separations coupled mass spectrometry operating under positive ESI mode. In the work presented here the applicability of SFC for both chiral and achiral bioanalysis is shown. The orthogonal separation selectivity compared with reversed-phase separations and tolerance for high organic sample compositions will be discussed. This work further presents a critical evaluation of the influence of mobile phase and make up flow modifiers on the sensitivity and selectivity of probe pharmaceuticals analyzed under SFC/ESI positive mode MS conditions.
Paul Rainville of Waters Corporation gave this Oral presentation at Pittcon 2015.
Current and Novel Immuno-Oncology Drug Evaluation Methods via Humanized Mouse...InsideScientific
Dr. Bin Xie discusses the current immuno-oncology drug development landscape, different humanized mouse models available for drug testing, and the investigation of potential mechanisms via imaging mass cytometry.
Since the first immune checkpoint blocker ipilimumab was approved by the US FDA in 2011, more drug companies have sought to develop their own immune therapy drugs. Humanized peripheral blood mononuclear cell (PBMC) reconstitution in immune deficient mice is becoming a valuable model for evaluating therapeutic antibodies, especially bispecific antibodies (BsAbs), which can mediate immune cells as well as target a tumor antigen.
However, this model has several drawbacks, including a limited dosing window due to graft-versus-host-disease and insufficient natural immune cell infiltration. This has hindered wide application of the model in the development of multiple immune checkpoint inhibitors or immune agonists.
To overcome these issues, LIDE has developed a unique human PBMC/cancer cell co-transfer model which can generate three-dimensional huPBMC-infiltrated tumor tissue for immunotherapy. This model has successfully been used to evaluate the biological function of several signaling proteins and biomarkers in multiple cancers, such as melanoma, breast cancer, and lung cancer.
In this webinar, Dr. Bin Xie discusses the current immuno-oncology drug development landscape, different humanized models available for drug testing, evaluates real-world case studies, and describes the investigation of potential mechanisms by imaging mass cytometry.
Key Topics Include:
- Introduction to immuno-oncology drug development and the importance of using humanized mouse models to address scientific questions
- Evaluation of current IO platforms and new methods from LIDE, including analysis of several case studies
- Understanding the spatiotemporal interaction between tissue-infiltrating immune cells and cancer cells via imaging mass cytometry
Similar to The Path from Chemical Tool to Approvable Drug (20)
Ohio State's ASH Review 2017 - Myeloproliferative DisordersOSUCCC - James
Katherine Walsh, MD
Assistant Professor of Clinical Internal Medicine
The Ohio State University Comprehensive Cancer Center -
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ohio State's ASH Review 2017 - Blood and Marrow TransplantationOSUCCC - James
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
The Ohio State University Comprehensive Cancer Center -
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ohio State's ASH Review 2017 - Benign HematologyOSUCCC - James
Spero R. Cataland, MD
Professor of Clinical Internal Medicine
The Ohio State University Comprehensive Cancer Center -
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ohio State's ASH Review 2017 - Update in MyelomaOSUCCC - James
Don M. Benson Jr., MD, PhD, FACP
Associate Professor of Medicine
Head of Translational Research
Division of Hematology
The Ohio State University Comprehensive Cancer Center -
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
ISI 2024: Application Form (Extended), Exam Date (Out), EligibilitySciAstra
The Indian Statistical Institute (ISI) has extended its application deadline for 2024 admissions to April 2. Known for its excellence in statistics and related fields, ISI offers a range of programs from Bachelor's to Junior Research Fellowships. The admission test is scheduled for May 12, 2024. Eligibility varies by program, generally requiring a background in Mathematics and English for undergraduate courses and specific degrees for postgraduate and research positions. Application fees are ₹1500 for male general category applicants and ₹1000 for females. Applications are open to Indian and OCI candidates.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
3. ‘END TO END’ INTEGRATED DRUG DISCOVERY
3 EVERY STEP OF THE WAY
B/D
Molecular
Biology
Cell Line
Generation
FBDDStructural
Biology
CRISPR
Adenoviral
Platform Human 1o Cells
Functional
Genomics
Library
Design
Analytical &
Purification
Process
ChemistryCADD
Synthetic
Chemistry
Formulation
Pharmaceutics
Chemo-
genomics
D/P
S/I
Safety
Assessment
Safety
Pharmacology
Non-GLP/GLP
Toxicology
Anatomic &
Clinical Pathology
Imaging
Animal Model
Development
Large Animal
Efficacy Models
Discovery
Pathology
In Vivo
Efficacy
In Vivo
Validation
PK/PD
Dose to Human
Predictions
ADME
Bioanalysis
Targets
Clinical
Candidate
Pharmacology
in vitro/in vivo
Hit Finding:
HTS, HCS
IND Enabling
Studies
Medicinal
Chemistry
Biomarker
Development
Target
Discovery
& Validation
DP DP
Ch
Discovery Pathway
Chemistry
Biology/ Discovery Technologies
DMPK/Pharmacology/Safety/
In vivo models
5. BEGIN WITH THE END IN MIND!
Properties of Drug-Like Molecules
5 EVERY STEP OF THE WAY
• Potent
• Modulate the target in a predictable way
• Selective
• How selective is selective enough?
• Formulatable
• Reasonable synthetic route or method of
production
• Good safety profile
• Understanding of toxicity
• No such thing as a “magic” therapeutic index
• Well-behaved pharmacokinetics
• PK relates to the pharmacodynamics
• Amenable to QD dosing (BiD acceptable in
some cases)
• Rapid, predictable onset of action
• Consistent metabolism
• Clearance is important
• No accumulation
• Understand drug-drug interactions
• Available biomarker
6. THE FIRST PART OF THE JOURNEY
6 EVERY STEP OF THE WAY
• A chemical tool is a fit for purpose compound.
• “Good enough” with respect to potency, selectivity and PK
• Will never become a drug
• Should serve as a starting point for a synthetic chemistry strategy
• Must be modifiable in a sensible manner
• Shouldn’t have serious red flags (e.g. highly reactive intermediates)
• Should be able to provide proof of concept for the project
Identification of a Chemical Tool
7. Inhibition of Cyclin-Dependent Kinase-4:
A Targeted Approach to Cancer Therapy
A Case Study in Cancer Drug Discovery
Peter Toogood, David Fry, W. R. Leopold
CASE STUDY
Road from Tool to Approved Drug
8. Cyclin D
Cdk4/6
Cdk2
Cyclin E
E2F/DP1
Rb
The Eukaryotic Cell Cycle
Growth Factors
G0
P
P
G1
SG2
M
Transcription stops,
DNA replication starts
E2F/DP1
Rb
P
P
Rb
P
P E2F/DP1 Transcription
E2F/DP1
P
P
P
Rb
P
PCyclin A
P
P
Rb
P
P
P
P
Rb
P
P
Cdk1
Cyclin B
p16
p27
C. J. Sherr Science 1996, 274, 1672.
S. A. Ezhevsky et al. Mol. Cell. Biol. 2001, 21, 4773.
(Kip1)
(INK4a)
Cdk1
Cdk3
Cyclin A
Cdk2
HDAC
HDAC
9. RATIONALE FOR TARGETING CDK4/6
Beginning with the End in Mind
• Most human tumors are deregulated in some part of the
Cyclin D/CDK4/p16/Rb/E2F pathway:
• e.g. p16 deletion, cyclin D over-expression, Rb phosphorylation, Rb deletion
• Inhibition of CDK4/6 will restore cell cycle control at the G1 checkpoint
• CDK4/6 inhibition anticipated to be cytostatic not cytotoxic
• Rb-deleted tumors not anticipated to be sensitive
11. Crystal Structure of PD 0172803 Bound to Cdk2
0.00 0.10 0.20 0.30
40 nM
20 nM
10 nM
control
1 / [ATP](mM)
1
Rate of pRb
phosphorylation
Increasing
[Inhibitor]
0.5
1.0
1.5
2.0
INHIBITORS ARE ATP-COMPETITIVE
Understanding Mechanism
12. Electron donating, polar
substituents provide optimal
potency and physical
properties
Cycloalkyl groups preferred
over alkyl- or aryl-
substituents
Are any substituents
tolerated here?
M. Barvian et al. J. Med. Chem. 2000, 43, 4606.
N
N NHN O
N
N
H
5
6
2
8
PD 0205606
INITIAL OPTIMIZATION FOR POTENCY
A Rational Synthetic Strategy
13. N
N NHN O
N
N
H
2 8
0205606
Cdk4/D:
Cdk2/A:
FGFr:
HCT-116:
IC50 (µM)
0.006
0.015
0.081
0.138
PD 0205606 is a potent Cdk inhibitor
with reasonable solubility (0.12 mg/mL)
But….
CL = 142 mL/min/Kg
AUC (PO) = 145 ng/hr/mL
t 1/2(PO) = 1.6 h
Loss of selectivity!
Poor Pharmacokinetics!
THE FIRST CHEMICAL TOOL
14. PD 0202020
Cdk4/D IC50 = 0.720 µM Cdk1/B
IC50 = 0.193 µM
Cdk2/A IC50 = 0.012 µM
Cdk2/E IC50 = 0.218 µM
PDGFr IC50 = 10.82 µM
FGFr IC50 = 3.900 µM
cSrc IC50 = 7.150 µM
A potent inducer of apoptosis in
HT-29 colon carcinoma cells
Metabolized at C5-C6 double bond
N
N NHN O
N
5
6
O O
O
p450
Proposed biotransformation
ENGINEERING OUT METABOLIC LIABILITY
15. N
N NHN O
N
N
H
5
6 N
N NHN O
N
N
H
0205606
Cdk4/D IC50 = 0.006 µM
Cdk2/A IC50 = 0.024 µM
FGFr IC50 = 0.081 µM
PDGFr IC50 = 0.5 µM
0217048 (R = H)
Cdk4/D IC50 = 0.014 µM
Cdk2/A IC50 > 5 µM
FGFr IC50 = 4.23 µM
PDGFr IC50 = 1.81 µM
2
R
• Substituents at C5 larger than methyl are not tolerated
• Effect of the C5 methyl group is modified by the C6 substituent
R Cdk4/D
IC50(µM)
Cdk1/B
IC50(µM)
Cdk2/A
IC50(µM)
Cdk2/E
IC50(µM)
Et 0.025 4.119 1.538 1.650
Cl 0.016 >5 1.625 1.500
Br 0.005 2.615 0.439 0.950
Ac 0.002 >5 0.230 1.15
CO2Et 0.006 >5 >5 >5
ATTACKING THE C5 – C6 POSITION
C5-Methylation Affords Cdk4 Selectivity
16. N
N NHN O
N
N
H
O
PD 0326562
Enzyme IC50 (µM)
Cdk4/D
Cdk1/B
Cdk2/A
Cdk2/E
FGFr
PDGFr
VEGFr
Lck
MDA-MB-435
0.002
>5
0.23
1.15
3.39
3.10
1.69
1.744
IC50 = 0.03 µM
PD 0326562 is efficacious at 75 mg/Kg but has a narrow
therapeutic index with significant toxicity at 100 mg/Kg
HOW SELECTIVE IS SELECTIVE ENOUGH ?
17. 0174413
Cdk4/D:
Cdk2/A:
0.210 µM
0.012 µM
0204661
Cdk4/D:
Cdk2/A:
0.092 µM
0.002 µM
0205783
Cdk4/D:
Cdk2/A:
0.145 µM
5.010 µM
N
N NHN O
N
N NHN O
N
N
N NHN O
N
PD 0204661 is toxic…..
but PD 205783 is somewhat selective for Cdk4
UNDERSTANDING TOXICITY
A Re-examination of the Pharmacophore
18. N
N NHN O
N
N
H
2 8
6 Br
N
N NHN O
N
N
N
H
Br
Rat PK
CL = 53 mL/min/Kg
IV t1/2 = 2 h
F = 10%
Enzyme IC50 (µM)
Cdk4/D
Cdk1/B
Cdk2/A
Cdk2/E
FGFr
PDGFr
0.016
>5
>5
>5
1.16
4.36
0325056 causes a clean G1 arrest up to 10.0 µM
0221933 0325056
DISCOVERY OF EXQUISITE SELECTIVITY OF CDK4
21. Cell Line Cell Type Rb IC50 (µM)
MDA-MB-435 Breast Carcinoma + 0.16
ZR-75-1 Breast Carcinoma + 0.17
T-47D Breast Carcinoma + 0.04
MCF-7 Breast Carcinoma + 0.10
H1299 Lung Carcinoma + 0.12
Colo205 Colon Carcinoma + 0.13
CRRF-CEM Acute lymphoblastic
leukemia (ALL)
+ 0.25
K562 CML + 0.40
MDA-MB-468 Breast Carcinoma - >3 (20%)
H2009 Lung Carcinoma - >3 (0%)
IN VITRO ACTIVITY OF PD0332991
Dependence on Rb
22. Biological Effect
Rb phos. (Ser780)
Cellular Proliferation
Initiate G1 arrest
IC50 (µM)
0.066
0.032
0.040
Data obtained using MDA-MB-435 and MDA-MB-453 breast carcinoma cell lines
RELATING TARGET MODULATION TO BIOLOGICAL EFFECTS
Target Biomarker Correlates with Biological Effects
23. 1
10
100
1000
10000
0 5 10 15 20 25 30
Time (Hours)
Subject Rat05
Subject Rat06
Subject Rat07
Subject Rat08
Mean Data
Individual and Mean Plasma 0332991 Concentration-Time Profiles
Following a Single 20 mg/kg PO Dose to Fasted Male Sprague-Dawley Rats
Time (h)
Concentration(ng/mL)
t1/2 = 2.8 h
F = 56%
PD 0332991 IS ORALLY BIOAVAILABLE
Well Behaved PK Profile
24. Days Post Tumor Implant
20 30 40 50
MedianTumorMass(mg)
150
200
250
300
400
500
600
700
800
900
1500
100
1000
control
36 mg/kg
58 mg/kg
93 mg/kg
150 mg/kg
240 mg/kg
Rx days:12-39
Route: Oral
Schedule: Q1D
Duration of therapy
PD0332991 INHIBITS TUMOR GROWTH IN VIVO
MDA-MB-435 Breast Cancer Line
25. Days Post Tumor Implant
20 25 30 35 40 45 50 55 60 65 70 75 80 85
MedianTumorMass(mg)
60
70
80
90
150
200
250
300
400
500
600
700
800
900
100
1000
control
12.5 mg/kg
37.5 mg/kg
75 mg/kg
150 mg/kg
Rx days:18-31
Route: Oral
Schedule: Q1D
Limit of palpation
Duration
of therapy
PD0332991 INHIBITS TUMOR GROWTH IN VIVO
Colo-205
26. MedianTumorMass(mg)
Days Post Implant
Daily PO Therapy
MDA-MB-468
60
70
80
90
100
200
300
400
20 25 30 35 40 45 50 55 60
Control
240 mg/kg (3/10 NSD)
150 mg/kg
75 mg/kg mg/kg
37.5 mg/kg
PD0332991 IS INACTIVE IN Rb NEGATIVE TUMORS
Predicted by Hypothesis
27. DEVELOPMENT OF PD 0332991 FOR CLINICAL USE
Observed Clinical Toxicity is Exaggerated Pharmacology
PD 0332991 was nominated for development in 2002
An Investigational New Drug application was filed in 2003
Phase I clinical trials commenced in 2004
2007 ASCO Annual Meeting Abstract (J. Clin. Oncology 2007, 25, no. 18S)
A Phase I Dose Escalation Trial of Daily Oral CDK4/6 Inhibitor PD 0332991
O’Dwyer et al
- Principal and dose-limiting toxicity is myelosuppresion.
- Of patients receiving PD 0332991 for 21 days in a 28 day cycle, MTD = 125 mg QD.
- 6 patients achieved stable disease, 3 of them for at least 20 cycles (breast, colon, ovarian)
28. CLINICAL ACTIVITY AGAINST ER-POSITIVE BREAST CANCER
Promising Early Results
ASCO Annual Meeting, Abstract no. 3060 (J. Clin. Oncology 2010, 28, 15s)
Phase I/II Study of PD 0332991 and Letrozole in ER-Positive Breast Cancer
Slamon et al
PD 0332291 (125 mg) QD for 21 days of a 28 day cycle with letrozole 2.5 mg QD
• 12 Patients enrolled (post-menopausal, ER-positive, HER-2 negative)
• 3 Patients discontinued due to disease progression
• DLT = grade 4 neutropenia
• 3 Patients with partial response
• 9 Patients with stable disease
29. PHASE I CLINICAL DATA IN MULTIPLE MYELOMA
Other Indications
52nd ASH Annual Meeting, Abstract 860. Lentzsch et al.
• A Phase I Study of PD 0332991: Complete CDK4/6 Inhibition and Tumor Response in Sequential Combination with
Bortezemib and Dexamethasone for Relapsed and Refractory Multiple Myeloma
• Schedule B: Patients received PD 0332991 (100 or 125 mg) QD days 1-12 of a 21 day cycle, with (IV) bortezomib and
(oral) dexamethasone administered on days 8, 11, 15 and 18.
“Encouraging antitumor activity was observed in this heavily treated MM population”
Of 12 patients receiving schedule B , there was one partial response , three patients with stable disease (≥ 3 months)
and one very good partial response with a patient who had relapsed on lenalidomide, bortezomib, and carfilzomib
therapies and a stem cell transplant
30. WE HAVE A DRUG!!!
30
Pfizer’s Palbociclib (PD-0332991) Receives Food And Drug
Administration Breakthrough Therapy Designation For Potential
Treatment Of Patients With Breast Cancer
Wednesday, April 10, 2013 8:00 am EDT
The U. S. Food and Drug Administration granted accelerated approval to
palbociclib (IBRANCE, Pfizer, Inc.) for use in combination with letrozole for
the treatment of postmenopausal women with estrogen receptor (ER)-
positive, human epidermal growth factor receptor 2 (HER2)-negative
advanced breast cancer as initial endocrine-based therapy for their
metastatic disease.
February 3, 2015
31. OTHER TUMOR TYPES IN CLINICAL STUDY
31
Development Continues
•Various Stages (I-II)
• Mantle Cell Lymphoma
• Refractory GIST
• NSCLC
• Glioblastoma
• Liver
33. Summary
• Selective CDK4/6 inhibition was hypothesized to present a safer
approach to treating Rb-positive tumors with a deregulated cell cycle
• PD 0332991 was discovered as a result of a concerted effort to identify
CDK4/6-selective kinase inhibitors by employing a number of chemical
tool compounds throughout the process.
• PD 0332991 was advanced to human clinical trials on the basis of
broad-based antitumor efficacy vs Rb-positive human xenograft tumors
in mouse models and its preclinical safety profile
• FDA has granted breakthrough status to the compound for the
treatment of breast cancer.
• Additional studies ongoing for treatment of other malignancies.
34. CONTACT US
J. A. Cornicelli, Ph.D., F.A.H.A.
251 Ballardvale Street
Wilmington, MA
01887
askcharlesriver@crl.com
www.criver.com
877.CRIVER.1