Posts Tagged ‘small molecule’

Reporter: Aviva Lev-Ari, PhD, RN

September 24 – 26, 2013

Westin Boston Waterfront

Boston, MA

About the Functional Genomics Screening Event:

In the screening world there is definitely no one-size fits- all and no dearth of options to choose from in terms of assay platforms, protocols, cells or reagents. So how do you decide which screening strategy will work best for you? Can different screening techniques be utilized in tandem or be staggered to better validate results and overcome inherent shortcomings? Which type of screen will provide information that is most accurate and physiologically relevant to your biological query? Cambridge Healthtech Institute’s tenth annual conference on Functional Genomics Screening Strategies will cover the latest in the use of RNA interference (RNAi) screens, combination (RNAi and small molecule) screens, chemical genomics and phenotypic screens, for identifying and validating new drug targets and exploring unknown cellular pathways. The first half of the conference will focus on the design and use of RNAi screens, while the second half will explore the use of chemical genomics and long non-coding RNA (LncRNA) screens and the transition into advanced cellular models such as, 3D cell cultures and stem cells that will launch the next-generation of functional screens. Screening experts from pharma/biotech as well as from academic and government labs will share their experiences leveraging the utility of such diverse screening platforms and models for a wide range of applications


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Reporter: Aviva Lev-Ari, PhD, RN

Nobel Laureate Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry

Word Cloud by Daniel Menzin

Drug Discovery Chemistry

Optimizing Small Molecules for Tomorrow’s Therapeutics

April 16-18, 2013 | San Diego, CA

Conference Brochure


Nobel Laureate Jack Szostak to Present Plenary Keynote at Eighth Annual Drug Discovery Chemistry Conference on April 16 – Record Attendance from More than 225 Organizations and 25 Countries is Expected

Drug Discovery Chemistry is one of the few conferences for medicinal chemists working in pharma and biotech, and is focused on discovery and optimization challenges of small molecule drug candidates. New this year are Constrained Peptides and Macrocyclics and GPCR-Based Drug Design which represent areas of chemistry where evolving technologies are leading to renewed interest. They complement the most popular meetings from the past few years: Anti-Inflammatories, Fragment-Based Drug Discovery, Kinase Inhibitor Chemistry and Protein-Protein Interactions:

 – Anti-Inflammatories  [View Agenda] 4/16-17

– Fragment-Based Drug Discovery  [View Agenda] 4/16-17

– Constrained Peptides and Macrocyclics Drug Discovery  [View Agenda] 4/16-17

– Kinase Inhibitor Chemistry  [View Agenda] 4/17-18

– Protein-Protein Interactions  [View Agenda] 4/17-18

– GPCR-Based Drug Design  [View Agenda] 4/17-18

In a recent interview with Bio-IT World’s Kevin Davies, Dr. Szostak shared his thoughts on evolutionary chemistry, cyclic peptides, discovery of new small molecules for therapeutics, and his upcoming plenary keynote address: mRNA Display: From Basic Principles to Macrocycle Drug Discovery.


Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry on

mRNA Display: From Basic Principles to Macrocycle Drug Discovery.


Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry

In a recent interview, nobel laureate Dr. Jack Szostak shared his thoughts with Bio-IT World’s Kevin Davies on evolutionary chemistry, cyclic peptides, discovery of new small molecules for therapeutics, his upcoming plenary keynote address, and much more. On April 16, at the Eighth Annual Drug Discovery Chemistry conference, Dr. Szostak will present mRNA Display: From Basic Principles to Macrocycle Drug Discovery.

For VIDEO of Doug Treco Discusses Constrained Peptides and Macrocyclics



Dr. Doug Treco, president & CEO of Ra Pharmaceuticals, shares recent developments in constrained peptides, macrocyclics, and how to develop peptides into a more useful class of drug. Dr. Treco will present Direct Selection of Cyclomimetics™ from mRNA Display Libraries at the Eighth Annual Drug Discovery Chemistry conference in San Diego on April 17.

List of Attendees:

Record Attendance Expected this Year! Should your Organization be on this List?
(Partial List as of 4/5)

A Star – Head – Organic Chemistry
Abbvie – Scientist – Research
Abbvie Bioresearch Ctr – Sr Scientist III – Chemistry
Abbvie Bioresearch Ctr – Sr Scientist III
AbbVie Inc – Principal Research Scientist
AbbVie Inc – Sr Scientist III – Molecular Modeling
Actelion Pharmaceuticals Ltd – Lab Head – Medicinal Chemistry
Actelion Pharmaceuticals Ltd – Sr Lab Head
Activ Motif – PostDoctoral Assoc
Addex Therapeutics – Assoc Res Dir – Structural Science
Adnexus a Bristol Myers Squibb R&D Co – Staff Scientist – Discovery
Affymax Inc – Sr Scientist II
Aileron Therapeutics Inc – Sr VP & CSO
Ajinomoto Co Ltd – Sr. Researcher
Allergan Inc – Sr Scientist – Medicinal Chemistry
Amakem NV – CoFounder & Dir External R&D – External R&D
Ambrx Inc – CTO
Amgen Inc – Principal Scientist – Pharmacokinetics & Drug Metabolism
Amgen Inc – Sr Scientist – Protein Technologies
AMRI – Dir Discovery R&D – Chemistry
AnalytiCon Discovery LLC – Exec VP Bus Dev – Natural Products
Anaspec Inc – Sr Chemist
Ardea Biosciences Inc – VP Research – Research Operations
Arena Pharmaceuticals – Research Fellow
Argenta Discovery 2009 Ltd – Sr Dir Chemistry
ARIAD Pharmaceuticals Inc – Assoc Dir Chemistry
Array BioPharma Inc – Sr Dir Cellular & Translational Biology
Asahi Kasei Pharma Co Ltd – Researcher – Lab for Medicinal Chemistry
Astellas – Scientist – Drug Discovery Research
Astellas Research Institute of American LLC – Principal Scientist – Med Chem
AstraZeneca – Assoc Principal Scientist – R&I iMed Medicinal Chemistry
AstraZeneca R&D Moelndal – Project Leader & Principal Scientist – Medicinal Chemistry & CVGI iMed
Axikin Pharmaceuticals Inc – Sr Dir Drug Dev Technologies – Drug Dev Technologies
Bayer AG – Principal Scientist
Bayer HealthCare AG – Computational Chemistry
Beijing Hanmi Pharmaceutical Co Ltd – Grp Leader Medicinal Chemistry & Analytical Chem
Ben Gurion Univ – Assoc Prof – Microbiology & Immunology & Health Sciences
Bicycle Therapeutics Ltd – CSO
Bio Rad Labs – Sales Mgr
Biogen Idec Inc – Principal Scientist – Physical Biochemistry
Biogen Idec Inc – Principal Scientist
Biogen Idec Inc – Scientist II – Medicinal Chemistry & Drug Discovery
Biogen Idec Inc – Sr Scientist & Medicinal Chemist
Biotage LLC – Specialist – Peptide Applications
Boehringer Ingelheim Pharma – Principal Scientist – Structural Research
Boehringer Ingelheim Pharma – Sr Principal Scientist – Medicinal Chemistry
Boehringer Ingelheim Pharma – Sr Scientist – Medicinal Chemistry
Boehringer Ingelheim Pharma GmbH & CO KG – Scientist – Chemical Research
BPS Bioscience Inc – Sr Research Scientist I
Brigham & Womens Hospital – Asst Prof Neurology
Bristol Myers Squibb – Grp Leader – Medicinal Chemistry
C&C Research Labs – Sr Research Scientist – Medicinal Chemistry
C&C Research Labs – Sr Researcher – CADD
Cancer Research UK Beatson Labs – Head – Chemistry
Catholic Univ of Korea – Prof – Natl Lab for Molecular Virology
Celgene – Assoc Scientist – Chemistry
Celgene – Sr Scientist – Chemistry
Celgene Avilomics Research – Sr Dir Chemistry
Celgene Corp – Sr Principal Investigator – Translational Dev
Cell Assay Innovations LLC – Founder & President
Charnwood Molecular Ltd – Head – Medicinal Chemistry
Charnwood Molecular Ltd – Mgr – Bus Dev
ChemAxon – Account Mgr
ChemAxon Ltd – Dir – Sales
ChemAxon Ltd – Principal Application Scientist
ChemBridge Corp – Exec Dir Sales & Marketing
Chemical Computing Group Inc – Principal Scientist – Scientific Support
Chinese Academy of Science – Guangzhou Institute of Biomedicine & Health
Chugai Pharmaceutical Co Ltd – Medicinal Chemist – Research
Chugai Pharmaceutical Co Ltd – Researcher
City of Hope Beckman Research Institute – Prof – Immunology
City of Hope Natl Medical Ctr – Staff Scientist – Molecular Medicine
CMD Bioscience LLC – Dir – Bus Dev
CMD Bioscience LLC – Dir Computational Chemistry
CNRS – Principal Investigator – Cancer Research
CNRS IPBS – Chemistry
Computype Inc – Market Mgr – Life Sciences
Computype Inc – Regional Sales Mgr
Cubist Pharmaceuticals Inc – Sr Scientist – Discovey Chemistry
Daiichi Sankyo Co Ltd – Assoc Sr Researcher – Discovery Research Lab
Daiichi Sankyo Co Ltd – Assoc Sr Researcher – Lead Discovery & Optimization Research Labs I
Daiichi Sankyo Co Ltd – Sr Dir – Lead Discovery & Optimization Research Labs I
Dart NeuroScience LLC – Assoc Dir – Chemistry
Dart NeuroScience LLC – Assoc Dir Chemistry
Dart NeuroScience LLC – Scientist II
Dart NeuroScience LLC – Scientist III – Leade Discovery HTS
Dart NeuroScience LLC – Scientist III
Dart NeuroScience LLC – Senior Research Assoc – Chemistry
Dart NeuroScience LLC – Sr Research Assoc – Chemistry
DEL BioPharma – Owner
DiscoveRx Corp – Dir Marketing – LeadHunter
DiscoveRx Corp – Sr Product Mgr
Dong A Pharmaceutical Co Ltd – Research Scientist
Dotmatics Ltd
E Merge Tech Global Svcs – CEO
E Merge Tech Global Svcs – Mgr – R&D
Eisai Co Ltd – Researcher – Product Creation
Eli Lilly & Co – Computational Chemist & Crystallographer
Eli Lilly & Co – Endocrine
Eli Lilly & Co – Sr Advisor – DCR&T
Eli Lilly & Co – Sr Research Advisor – Discovery Chemistry
Eli Lilly & Co – Sr Research Advisor – Discovery Chemistry Research
Eli Lilly & Co – Sr Research Scientist – Discovery Chemistry
EMD Serono Research & Development Institute Inc – Chemistry
EMD Serono Research & Development Institute Inc – Head – Drug Target Innovation & External Innovations
EMD Serono Research & Development Institute Inc – Sr Scientist – Chemistry
EMD Serono Research & Development Institute Inc – Sr Scientist – Medicinal Chemistry
Emory Univ – Post Doc Fellow
Ensemble Therapeutics – CSO
Entelos Inc – Dir Marketing
ESBS – Research Dir Receptord & Membrane Proteins – CNRS Biotechnology
ETH Zurich – Sr Scientist – Pharmaceutical Sciences
Evotec Inc – Project Leader – Discovery
Ewha Womans University – Prof
F Hoffmann La Roche Inc – Consultant – Medical Affairs
F Hoffmann La Roche Inc – Sr Research Leader – PR&D Discovery Chemistry
F Hoffmann La Roche Inc – VP & Global Head of Discovery Technologies – pRED & Discovery Technologies
Ferring Research Institute – Sr Scientist – Medicinal Chemistry
FLAMMA – Dir – Bus Dev
Full Spectrum Genetics Inc – Head – Bioinformatics
GE Healthcare – Product Specialist
Genentech Inc – Assoc Dir Structural Biology
Genentech Inc – Postdoc Research Fellow – Structural Biology
Genentech Inc – Scientist – Medicinal Chemistry
Genentech Inc – Scientist – Protein Engineering
Genentech Inc – Scientist & Team Leader – Medicinal Chemistry
Genentech Inc – Sr Mgr – Bus Dev
Genomics Institute of the Novartis Research Foundation – Principal Investigator – Structural Biology
Gilead Sciences Inc – Dir Biology
Gilead Sciences Inc – Dir Medicinal Chemistry
Gilead Sciences Inc – Research Scientist II
GL Chemtech Intl Ltd – Dir Bus Dev
Gwangju Institute of Science & Technology – Prof – Life Sciences
Harvard Medical School – Hematology Oncology
Hauptman Woodward Institute – Sr Research Scientist – Structural Biology
Helmholtz Zentrum Muenchen GmbH – Head – Assy Dev & Sxcreening Platform
Helsinn Therapeutics Inc – Sr Assoc – Tech Affairs
Heptares Therapeutics Ltd – Head – Biomolecular Structure
Hewlett Packard Oregon
Imgenex Corp – Principal Consultant – Corp Dev
Imgenex Corp – Product Mgr – Marketing
In Silico Biosciences – CSO – Computational Neuropharmacology
Indiana University – Research Asst Prof – Biochemistry & Molecular Biology
Industry Canada – Sr Patent Examiner – Organic 02
INSERM – Principal Investigator – CRCM CNRS
Integral BioSciences – Research Scientist – Med Chem
Iowa State University – Principal Investigator – Biomedical Sciences
Ironwood Pharmaceuticals Inc – MedChem
Janssen Pharmaceuticals Inc – Sr Scientist – Scale Up Synthesis
Japan Tobacco Inc – Research Scientist – Central Pharmaceutical Research Lab
Japan Tobacco Inc – Researcher
Japan Tobacco Inc – Sr Dir Project & Portfolio Mgmt – Project & Portfolio Mgmt
Johns Hopkins University – Prof – Biology
Johnson & Johnson Pharmaceutical R&D – Assoc Scientist – Chemistry
Johnson & Johnson Pharmaceutical R&D – Chemist – Med Chem
Johnson & Johnson Pharmaceutical R&D – Physiological Systems
Johnson & Johnson Pharmaceutical R&D – Principal Scientist – Immunology Chemistry
Johnson & Johnson Pharmaceutical R&D – Sr Scientist – Chemistry
JT Central Pharmaceutical Research Institute – Research Scientist – Chemistry
Jubilant Discovery
Kalexsyn Inc
King Saud University – Pharmaceutical Chemistry
Korea Research Institute of Chemical Technology – Principal Researcher Drug Discovery Research
Lexicon Pharmaceuticals – Assoc Dir – Chem Tech
Life Chemicals Inc – Mgr – Bus Dev & Sales
Life Chemicals Inc – VP Marketing & Sales
LipoScience – CSO
Los Alamos Natl Lab – PostDoc Research Assoc – Bioscience
Lundbeck Research USA – Principal Scientist – Discovery Chemistry & DMPK
Massachusetts General Hospital – Prof – Genetics
Mayo Clinic – Asst Prof – Immunology
Medivation Inc – Dir Medicinal Chemistry
Merck – Principal Scientist
Merck Serono Research – Sr Dir Lead Discovery Technologies – MS DTC Strategic Operations Global Tech
Mitsubishi Tanabe Pharma Corp – Research Scientist – Medicinal Chemistry
MorphoSys AG – Sr Scientist
Natl Institute of Biological Science – Sr Investigator
Natl Taiwan University – Research Assoc – Chemisty
Natl Univ of Singapore – Assoc Prof – Chemistry
NIH NCATS – Research Scientist – Probe Dev Ctr
NIH NINDS – Investigator – Basic Neuroscience
Novartis Institute for Tropical Diseases Pte Ltd – Investigator III – Chemistry
Novartis Institutes for BioMedical Research Inc – Dir Bus Dev
Novartis Institutes for BioMedical Research Inc – Presidential Postdoctoral Fellow
Novartis Pharma AG – Investigator III – Global Discovery Chemistry
Novartis Pharma AG – Proteomic Chemistry
Novartis Pharma AG – Research Investigator – NIBR
Nuevolution AS – Research Scientist
Nuevolution AS – Sr Scientist – Molecular Design
Oncodesign SA – CSO
Onyx Scientific Ltd – Dir Bus Dev
OpenEye Scientific Software Inc – Dir Emerging Markets – Emerging Markets
OpenEye Scientific Software Inc – Sr Applications Scientist
Ora Inc – Dir Pre Clinical Svcs
Original Biomedical Corp – Bus Dev
Peptron Inc – CEO
Pfizer Animal Health – Sr Principal Scientist
Pfizer Global R&D Groton Labs – Sr Principal Scientist – Structure Biology & Biophysics
Pfizer Inc – Assoc Dir – Prizer Animal Health
Pfizer Inc – Assoc Research Scientist – Chemical Sciences
Pfizer Inc – VP Chemistry
Pfizer Research Labs – Principal Scientist – Worldwide Medicinal Chemistry
PharmaCore Inc – Dir Bus Dev
PharmaCore Inc – President
Pharmacyclics Inc – Research Scientist III – Medicinal Chemistry
Polish Academy Of Sciences – Institute of Organic Chemistry
Polyphor Ltd – CSO & CoFounder
POSTECH – Assoc Prof
Prestwick Chemical – Head – Medicinal Chemistry
Prestwick Chemical – VP US Operations
Principia BioPharma Inc – Assoc Dir
Protagonist Therapeutics Inc – President & CEO
Purdue University – Assoc Prof – Medicinal Chemistry & Molecular Pharmacology
Quantum Tessera Consulting LLC – President and CSO
RA Pharmaceuticals Inc – President & CEO
RA Pharmaceuticals Inc – Scientist II
Receptos Inc – Assoc Dir – Biology
Receptos Inc – Dir Structural Biology
Receptos Inc – Scientist I
Roche Diagnostics GmbH – Dir Bio Analysis – Antibody Dev
Roche NimbleGen Inc – Sr Scientist
Rockefeller University – Richard M & Isabel P Furlaud Prof – Molecular Biology & Biochemistry
Rutgers University – Asst Research Prof – CABM
Sanofi Aventis – Head – In Silico Drug Discovery
sanofi aventis Grp – Project Leader
Santen Pharmaceutical – Researcher – Synthetic Chemistry Group
Schrodinger Inc – Applications Scientist
Science for Solutions LLC – President
Scripps Research Institute – Asst Prof – Molecular Biology
Scripps Research Institute – PostDoc Assoc – Molecular Therapeutics
Scripps Research Institute – Prof – Chemical Physiology
Scripps Research Institute – Research Assoc – Chemistry
Scripps Research Institute – Visiting Scientist – Chemical Physiology
Selcia Ltd – Grp Leader – Biology
Senomyx Inc – Principal Scientist – Chemistry
SENSIQ – CSO – Bioinstrumentation
SENSIQ – VP Marketing – Sales & Marketing
Shionogi & Co Ltd
SIGA Technologies Inc – CSO
Simulations Plus Inc – Research Fellow – Life Sciences
Simulations Plus Inc – Team Leader – Cheminformatics Study
Sookmyung Womens University – Student – College of Pharmacy
SRI Intl – Program Dir Medicinal Chemistry
St Jude Childrens Research Hospital – Post Doc Fellow – Chemical Biology & Therapeutics
St Jude Childrens Research Hospital – Postdoc – Chem Bio & Therapeutics
St Jude Childrens Research Hospital – Research Asst – Chemical Biology & Therapeutics
St Petersburg State Institute of Technology – Lab of Molecular Pharmacology
Stanford University – Assoc Prof – Bioengineering
Stanford University – Graduate Student – Kobilka Lab
Stanford University – Research Assoc – Chemical & Systems Biology
Structural Genomics Consortium – Postdoc Research Assoc – Epigenetics Probes Team
Sygene Intl Ltd – Sr Lead Investigator – Medchem
Sygnature Discovery Ltd – CEO
Sygnature Discovery Ltd – Dir New Bus Dev
SYNthesis Shanghai – Managing Dir
Synthonix – Bus Dev Mgr
Synthonix – CoFounder & President & CEO
Taiho Pharmaceutical Co Ltd – Sr Scientist – Medicinal Chemistry
Takeda California – Assoc Scientist
Takeda California – Scientist – Discovery Biology
Takeda California – Sr Scientist – Chemistry
Takeda California – Sr Scientist – SB & Ab Core Science & Technology
Takeda Pharmaceutical Co Ltd – Principal Scientist – Structural Biology
Takeda Pharmaceutical Co Ltd – Researcher – Medicinal Chemistry Lab
Takeda Pharmaceutical Co Ltd – Researcher – Pharmaceutical Research
Takeda San Diego – Dir Immunology Chemistry
Takeda San Diego – Scientist II
TC Scientific Inc – CEO
Theravance Inc – Research Assoc – Medicinal Chemistry
Theravance Inc – Scientist – Med Chem
Theravance Inc – Sr Research Advisor – Medicinal Chemistry
Theravance Inc – VP Molecular & Cellular Biology
Thermo Fisher Scientific Inc – Bus Mgr
Topharman USA
Tranzyme Pharma Inc – Sr VP Research & Preclinical Dev
Tranzyme Pharma Inc – VP IP & Operations
Tsinghua Univ – Medicinal Chemistry
UCB Pharma – Principal Scientist – CADD
UCB Pharma – Computational Medicinal Chemist
University of California Los Angeles – Prof – Molecular Imaging
University of California San Diego – Asst Prof – Chemistry & Biochemistry
University of California San Diego – Postdoc – Chemistry & Biochemistry
University of California San Diego – Prof – Clinical Medicine & Rheumatology
University of California San Diego – Prof – Molecular Biology
University of California San Francisco – Assoc Adjunct Prof – Lab Medicine
University of Central Florida – GRA – Chemistry
University of Cincinnati – Assoc Prof – Environmental Health
University of Essex – Prof – Computational Chemistry
University of Illinois Chicago – Prof – Biopharmaceutical Sciences
University of Maryland Baltimore – Grollman Glick Prof – Pharmaceutical Sciences
University of Miami – Dir Drug Discovery – Diabetes Research Institute
University of Navarra – Dir – Small Molecule Discovery
University of New South Wales – Postgraduate Student – Chemistry
University of Paris Diderot – Sr Research Assoc – Inserm UMR S973
University of Pittsburgh – Prof & Chair – Microbiology & Molecular Genetics
University of Pittsburgh – Research Asst Prof – Computational & Systems Biology
University of Southern California – Assoc Prof – Pharmacology & Pharmaceutical Sciences
University of Southern California – Scientist – Molecular & Computational Biology
University of Southern California – Molecular Microbiology & Immunology
University of Texas Dallas – Assoc Prof – Psychiatry & Neurology & Neurotherapeutics
University of Texas Houston – Asst Prof – Stem Cell Research
University of Toronto – Principal Investigator – Medical Biophysics
University of Utah – Research Assoc
University of Warsaw – Institute of Genetics and Biotechnology
University of York – Prof – Chemistry
University of Zurich – Scientist – Biochemistry
University Pompeu Fabra – Research Assoc – Medicinal Chemistry
Vanderbilt University – Research Fellow – Ctr for Neuroscience Drug Discovery
Vertex Pharmaceuticals Inc – Med Chem
Vertex Pharmaceuticals Inc – Research Fellow II – Biology
Vertex Pharmaceuticals Inc – Research Scientist – Chemistry
Vertex Pharmaceuticals Inc – Research Scientist I – Biology
Vidya Bharati College – Asst Prof – Chemistry
Vrije University Brussels – Exec Dir & Prof – Mol & Cellular Interactions
Vrije University Brussels – Prof Research Grp of Organic Chemistry – Bioengineering Sciences & Chemistry
Wayne State University – Research Scientist – Pathology & Oncology
Wichita State University – WSU Foundation Distinguished Prof – Chemistry
Wistar Institute – Staff Scientist
WuXi AppTec – Dir Bus Dev – Chemistry Svcs
X Chem Pharmaceuticals Inc – Dir Chemistry
X Chem Pharmaceuticals Inc – Sr Dir Lead Discovery
Yale University – Assoc Prof – Lab Medicine & Pharmacology
Yonsei University – Prof – Biochemistry
Yonsei University – Prof – Biotechnology

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FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules. Author-Writer: Stephen J. Williams, Ph.D.

This posting is a follow-up on the Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations post and gives a brief synopsis of the current state of FDA regulatory guidelines with respect to DART studies on small molecule (non-biological based) therapeutics.    The following is adapted from the book Principles and Methods of Toxicology by Dr. A Wallace Hayes (1) and is an excellent reference on reproductive toxicology and testing methods.

Chemical insult occurs to the human reproductive system at a multitude of stages in development and the life cycle, leading to the extensive testing which must be performed to diligently the reproductive and development toxicity of a chemical/drug.  Abnormalities and toxic manifestations in the offspring may result from insult to the adult reproductive (either female or male) and neuroendocrine systems, as well as damage to the embryo resulting in embryolethality, fetus at any period during organogenesis, juvenile development or, in the case of certain antibody therapies, immune system development.  The latter, toxic insult to the developing immune system could possibly be manifested as either an immune defect in the newborn or, later in life, as tolerance to said therapy.  It is estimated that exposure to the pregnant woman, of either environmental contaminants or drug, is significant.  It is estimated that a mother may be taking an average of 8-9 different drug preparations, mostly over the counter preparations such as antacids, vitamin preparations, cathartics etc. with the maximal drug intake occurring between 24 and 36 weeks of gestation.

Toxic insult to the developing embryo is dependent on

  • Fetal development stage during drug/chemical exposure
  • Maternal/placental xenobiotic metabolism
  • Pharmacokinetic parameters affecting bioavailability and fetal/maternal drug binding

The following table shows the dependency of developmental stage to teratogenicity: adapted from J. Manson, H. Zenick, and R.D. Costlow from Principles and Methods of Toxicology.

Developmental Stage Major Susceptibility
Preimplantation Embryolethality
Organogenesis Births defects; embryolethality
Fetal Growth retardation, fetal death, functional deficits
Neonatal Growth retardation, nervous system alterations, immune and endocrine systems

It is not generally accepted that there is a dose dependency of teratogenesis however most teratogens have specific mechanisms of action and teratogenic effects occur at much lower doses than result in maternal toxicity.   However, the developmental toxicity may be manifested later in life, including as reproductive toxicity affecting adult fertility and familial generations.

FDA Guidelines for DART Studies on Non-Biologics (Small Molecule Therapeutics)

The basic design for DART studies incorporate the aforementioned principles of tetralogy:

  • developmental stage of fetal exposure
  • parental effects on reproduction and development
  • toxicity may be manifested over multiple generations including fertility rates

Therefore two designs are generally used for DART studies

  1. exposure across several generations
  2. exposure during one generation

FDA requires one control group and two treatment groups, and evaluation of at least two species.  However, most studies will use two rodent and one nonrodent species.

Multigenerational Design

Multigenerational DART studies are conducted for compounds likely to concentrate in the body following long-term exposure.  Examples of types of compounds include pesticides and food additives.

Figure 1.  General Design of a Multigenerational DART study.  Weanlings (30-30 days of age) from the parental generation are treated for a period up to 60 days. At 100-120 days of parental generation, animals are mated.  Fx = filialx .

Three Segment, Single Generation Tests

The single generation design is more suitable for DART studies on drugs, as most therapeutic would be taken over short periods (during pregnancy) and have relatively short half-lives in the body.  FDA guidelines separate these studies in three phases:

I.            Phase I: evaluation of fertility and general reproductive performance

II.            Phase II: assessment of teratogenicity and embryotoxicity

III.            Phase III: peri- and postnatal evaluations.

All figures are adapted from Principles and Methods of Toxicology.(1)

FDA guidelines Guidance for Industry Reproductive and Developmental Toxicities —Integrating Study Results to Assess Concerns can be found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079240.pdf

FDA Guideline for reproductive toxicity testing for small molecule therapeutics can be found at:


1.            Hayes, A. W. (1986) Principles and Methods of Toxicology, Raven Press, New York

Other research papers on Pharmaceutical Intelligence and Reproductive Biology, Bio Insrumentation, Endocrinology Genetics were published on this Scientific Web site as follows

Non-small Cell Lung Cancer drugs – where does the Future lie?

Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

Leptin and Puberty

Gene Trap Mutagenesis in Reproductive Research

Genes involved in Male Fertility and Sperm-egg Binding

Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice

Pregnancy with a Leptin-Receptor Mutation

The contribution of comparative genomic hybridization in reproductive medicine

Sperm collide and crawl the walls in chaotic journey to the ovum

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

Biosimilars: CMC Issues and Regulatory Requirements

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Assisted Reproductive Technology Cycles and Cumulative Birth Rates

Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US

Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Guidelines for the welfare and use of animals in cancer research

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Targeting a protein important for chromatin organization could be a new strategy for male birth control. Proper regulation of chromatin dynamics is critical for proper sperm development, and mice with alterations in a protein that is central to chromatin organization are infertile. Now, scientists show that treating mice with a drug known to inhibit that protein impedes sperm development and renders the animals infertile—but halting treatment allows sperm production to restart and mice to sire normal litters.

The results, published in Cell, suggest that targeting this protein could produce a safe, reversible method for non-hormonal male contraception—a long-sought goal that has so far failed to materialize as an option alongside condoms and vasectomies.

Hormonal male contraception methods are already well-established. Male hormonal contraception works at least as well as a typical female oral contraceptive pill. But such contraceptives still have some significant hurdles to overcome before making it to market.

First, the strategy, which involves administering a hormone (usually a progestin) to halt production of testosterone and thus inhibit sperm development, does not suppress sperm production enough in every man. It also requires dosing with enough exogenous testosterone to maintain libido and muscle mass, but there’s currently no cheap and easily applied testosterone on the market. Furthermore, hormone-based male contraception can cause side effects. Unlike side effects for the female hormonal contraception, these can’t be balanced against the risks of pregnancy, which are often higher, noted John Amory at the University of Washington. Because men don’t run the same medical risks of pregnancy, there’s a higher bar for ensuring that contraception administered to healthy men doesn’t carry risks. Finally, despite worldwide surveys suggesting public receptiveness to a male contraceptive pill, pharmaceutical companies no longer fund development of such drugs.

Some of these issues have spurred researchers to look for a non-hormonal way to temporarily induce infertility in men, which should cause with fewer side effects and be more appealing to pharma. Amory’s work, for example, has shown that a compound that targets the retinoic acid pathway of sperm development reversibly inhibits sperm production. The drug’s potential is hamstrung by the fact that men taking the drug can’t consume alcohol without nausea—a side effect he’s currently working to circumvent.

The current study builds on previous work by Debra Wolgemuth at Columbia University showing that BRDT—a testes-specific member of a family of bromodomain-containing proteins, which are important for regulating chromatin organization in various tissues—was critical for normal sperm development in mice. Truncating BRDT has an amazing effect on haploid sperm development. Removing the first bromodomain results in production of a shortened protein and, consequently, the aberrant organization and packaging of DNA in the sperm cells produced. Spermatids fail to elongate normally in mutant mice, resulting in decreased sperm production, misshapen sperm, and infertility.

In order to test the possibility that a BRDT-inhibiting drug, JQ1, might have potential as a male contraceptive, Martin Matzuk of Baylor College of Medicine and his collaborators injected male mice daily with the drug, and examined their testis volume. This volume, which reflects the amount of sperm in the testes, dropped by 60 percent over the 6 weeks of treatment. The sperm count of these mice was nearly 90 percent lower than in control mice, and sperm motility also plunged in JQ1-treated mice, collectively resulting in infertility. Though JQ1 is known to inhibit related proteins expressed elsewhere in the body, the mice seemed to have no other effects from JQ1 treatment, and normal hormone levels in treated mice suggested that infertility wasn’t the result of a hormone imbalance.

A closer look at sperm generation in JQ1-treated mice suggested that sperm development was primarily blocked after the sperm cells had undergone meiosis, but before they began the process of elongating—a similar stage to that seen in BRDT-mutant mice. Importantly, the mice regained the ability to sire pups after several weeks off the drug.

The reversibility of the treatment is likely attributable to the fact that the researchers are targeting sperm cells midway through development, rather than accessory cells that support sperm development from stem cells, noted Michael Griswold, who studies sperm cell development at Washington State University, but did not participate in the study. It’s “a great place to inhibit, because you don’t get sperm cells, but you don’t affect stem cells, which makes [the treatment] reversible,” he explained.

Whether JQ1 acts by primarily targeting BRDT and derailing chromatin organization or whether it inhibits other family members expressed during sperm development remains unclear. Matzuk and his colleagues examined gene expression in JQ1-treated and control mice, and saw decreased expression of many genes important for meiosis, suggesting that JQ1 may be working by affecting transcription of a suite of important genes for spermatogensis. Also, because JQ1 also inhibits BRDT-related proteins, researchers need to be watchful for long-term side effects not detected in the current study, Matzuk noted. Going forward, it will be important to design drugs that selectively target BDRT.

Source References:




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