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Contains 3 Component(s) Includes a Live Web Event on 11/19/2024 at 11:00 AM (EST)
This symposium/webinar is intended to educate ADME scientists on MPS technology and its potential to generate clinically translatable data.
Despite billions in annual investment, most drugs never reach the market because preclinical experiments fail to predict human effects. In this webinar, we will cover why in vivo models only deliver an approximation of what is likely to happen in the human body and why building more predictive, human-relevant models is key to reducing drug attrition. During the webinar we will introduce ADME scientists to the field of microphysiological systems (MPS), also known as organ-on-a-chip (OOC).
We will explore how MPS technology can be implemented to create human-specific tissue models such as the gut and liver and interconnect them into systems that generate clinically translatable data. We will demonstrate how a deeper and earlier knowledge of human drug ADME profiles enables issues to be addressed prior to costly preclinical studies.
The webinar will conclude by highlighting how the complementary use of MPS bridges the human-relevance gap, facilitating the confident selection of safer and more effective drug candidates, whilst also reducing costs.
This webinar is sponsored by CN Bio Innovations.
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Contains 3 Component(s) Includes a Live Web Event on 11/12/2024 at 9:00 AM (EST)
In this webinar we will discuss efforts for improving the global underrepresentation of African genetics in science. We will further explore the current landscape and challenges in realizing an African hepatic modeling platform - with a specific focus on the development of hiPSC models that can better recapitulate hepatic function.
The African continent harbors unparalleled genetic diversity yet remains largely underrepresented in pharmaceutical research and development. Pharmacogenomics is fundamental to precision medicine strategies, and although to date largely absent from implementation, representing the genetic diversity of the African population within the laboratory is critical to the democratization of stratified and effective healthcare in Africa. Afrocentric preclinical resources could support precision medicine on the continent and reshape the global underrepresentation of African genetics in science. Models which could begin to address this include primary human hepatocytes, immortalized hepatic cell lines, and human induced pluripotent stem cell (hiPSC)derived hepatocyte-like cells – derived from individuals of African genetic ancestry. The feasibility of an African hepatic modeling platform is slowly being realized due to the convergence of several technologies and methodologies which have traditionally been siloed on the continent.
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Contains 3 Component(s) Includes a Live Web Event on 10/22/2024 at 9:00 AM (EDT)
The human genome comprises approximately 20,000 protein-coding genes and over 900 million variants according to dbSNP. Systematic understanding of the impact of genomic alterations in humans is critical for the development of effective medicines. However, it is simply not feasible to study every single variant in detail. This challenge extends to the analysis of how pharmacogenes are affected by genetic polymorphisms, as it is impossible to study the impact of every individual single nucleotide polymorphisms/variations (SNPs/SNVs) of pharmacogenes in human clinical trials. Yet, understanding drug metabolism and pharmacokinetics is crucial for assessing drug efficacy and safety. To minimize harmful side effects from drugs while maximizing their therapeutic effectiveness in each patient or group of patients, we would need to understand the effects of population specific SNPs in pharmacogenes and drug-enzyme interactions. To date the effect of non-synonymous SNPs, more specifically missense mutations, at the protein level is poorly studied in pharmacogenomics research. We previously proposed a post-hoc analysis approach of molecular dynamics (MD) simulations using dynamic residue network (DRN) analysis to consider the dynamic nature of functional proteins and protein-drug complexes and to probe the impact of mutations and their allosteric effects. This talk will discuss the computational approaches and tools that we have developed over the years with applications to pharmacogenomics.
The human genome comprises approximately 20,000 protein-coding genes and over 900 million variants according to dbSNP. Systematic understanding of the impact of genomic alterations in humans is critical for the development of effective medicines. However, it is simply not feasible to study every single variant in detail. This challenge extends to the analysis of how pharmacogenes are affected by genetic polymorphisms, as it is impossible to study the impact of every individual single nucleotide polymorphisms/variations (SNPs/SNVs) of pharmacogenes in human clinical trials. Yet, understanding drug metabolism and pharmacokinetics is crucial for assessing drug efficacy and safety. To minimize harmful side effects from drugs while maximizing their therapeutic effectiveness in each patient or group of patients, we would need to understand the effects of population specific SNPs in pharmacogenes and drug-enzyme interactions. To date the effect of non-synonymous SNPs, more specifically missense mutations, at the protein level is poorly studied in pharmacogenomics research. We previously proposed a post-hoc analysis approach of molecular dynamics (MD) simulations using dynamic residue network (DRN) analysis to consider the dynamic nature of functional proteins and protein-drug complexes and to probe the impact of mutations and their allosteric effects. This talk will discuss the computational approaches and tools that we have developed over the years with applications to pharmacogenomics.
Özlem Tastan Bishop
Özlem is full Professor in structural bioinformatics at Rhodes University, South Africa and distinguished adjunct Professor at Saveetha University, Chennai, India.
She received her BSc degree in Physics from Boğaziçi University, Istanbul, Turkey. Then she moved to the Department of Molecular Biology and Genetics at the same University for her MSc degree. She obtained her PhD from Max-Planck Institute for Molecular Genetics and Free University, Berlin, Germany in 2003. While doing her PhD, Özlem became interested in structural biology, and during her postdoctoral positions (Texas University, USA; University of Western Cape and University of Pretoria, South Africa) she gained experience in structural bioinformatics as well as structural biology.
In 2009, Özlem took up an academic position at Rhodes University, South Africa. She established the Research Unit in Bioinformatics (RUBi) in 2013. She has graduated 25 PhD and 38 MSc students since she joined Rhodes University. She received Rhodes University Internationalization award for 2018; Rhodes University Vice Chancellor’s Distinguished Senior Research award for 2020 and South African Society for Bioinformatics (SASBi) Silver Award, 2022.
She serves on the Editorial Board for PLOS Computational Biology, PLOS One and Frontiers in Molecular Biosciences and Frontiers in Applied Mathematics and Statistics, Biological Modeling and Simulation Section, and she is an Advisory Board member of F1000Research Bioinformatics Gateway. Özlem’s broad research interest is structural bioinformatics and its applications to drug design and development. Her recent interest is in the allosteric mechanisms of proteins and understanding the effects of nonsynonymous single nucleotide variations on protein structure and function in the context of drug resistance and drug metabolism. She has published roughly 100 research articles.
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Contains 3 Component(s) Includes a Live Web Event on 09/24/2024 at 10:45 AM (EDT)
The purpose of this webinar is to: 1. Provide valuable knowledge exchange between ADC developers andthe Regulatory Agency (FDA) 2. Hear from leading experts in PK/PD, pharmacometrics, & clinical pharmacology, plus clinicians and regulatory minds, fostering collaborations and partnerships that can propel ADC projects seamlessly. 2. Demonstrate the successful integration of pharmacokinetics and pharmacometrics in ADC clinical development, enhancing your ability to apply these principles to your own work
Quantitative pharmacology approaches can inform clinical development strategies for ADCs similar to how these approaches have been applied for decades for small and large molecules. Therefore, as long as a validated quantitative model is in place, principles of model-informed drug development (MIDD) can be applied to ADC/ARC/RIC as well. This would provide enormous value since it would circumvent conducting large and new trials and thus allow predicting efficacy when linker or payload or mAB optimized. It is clear that clinical pharmacology principles are paramount to answering clinical and regulatory questions throughout these ADC/ARC/RIC developments. Translation of therapeutic index, immunogenicity, efficacy and safety from preclinical species needs to be understood using the better relationship between Target abundance, biomarkers and efficacy/safety in preclinical species, and how this translates to the clinic. Together, these data-driven approaches should be embraced to accelerate the delivery of safe and efficacious ADC to patients globally.
Qin Sun
Dr. Qin Sun is the Therapeutic Biologics Program (TBP) Biologics Lead in the Office of Clinical Pharmacology (OCP), CDER, FDA. Her job functions include guide and support reviews and policy development for novel biologics and biosimilars. She also serves as vice chair for Biologics Oversight Board in OCP, and chair for several biologics and biosimilar guidance working groups. Qin joined FDA in 2016. Before that, she worked at Pharmaceutical Product Development (PPD) from 2015 to 2016, and at Bristol-Myers Squibb from 2008 to 2014. Qin received her PhD from University of Virginia. Her work experience extends from drug discovery to drug development, and finally to regulatory review, focusing on biologics and biosimilars currently.
Venkatesh Reddy
Dr. Venkatesh Pilla Reddy is a distinguished Senior Director in the Global PKPD and Pharmacometrics group at Eli Lilly and Company in the UK. His extensive expertise stems from earning his PhD in Pharmacometrics through a collaborative program involving Pfizer, Janssen Pharmaceuticals, and Merck via TI Pharma in the Netherlands. His doctoral research centred on the PKPD M&S of antipsychotic drugs, and he has since made substantial contributions to the Quantitative Pharmacology and Pharmacometrics groups at Merck and AstraZeneca.
At present, Venkatesh provides invaluable Clinical Pharmacology and Model-Informed Drug Development support for a range of impactful projects in oncology, neuroscience, and immunology. Notably, he played a pivotal role as Deputy Topic Leader position ICH shaping ICH DDI guideline. Furthermore, he plays a leading role in influential cross-industry working groups including IQ TALG, ISOP, ASCPT, and ISSX M&S. He also serves as an esteemed Editorial Board Member for the Biopharmaceutics and Drug Disposition Journal and is a respected reviewer for clinical pharmacology/PKPD M&S-related journals.
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Pharmacogenomics is relevant worldwide for modern therapeutics and yet needs further uptake in developing countries. There is paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and multiple drug treatments. To evaluate the role and impact of host underlying genetics on treatment response, different approaches are used depending on existing levels of understanding on the functional significance of genetic variants in question. This lecture showcases the work done pharmacogenomics research and how this has occurred in Africa and how “omics” is being leveraged. Our approach focuses on common disease conditions and commonly used medications including herbal medicinal plants. We report on antiretroviral therapy and other treatments alter microRNA expression signatures and expression of drug-metabolizing enzyme genes, in vitro. These data point to several important clinical implications through changes in drug/drug interaction risks and achieving optimal therapeutics. Thus, differential expression of microRNAs after treatment with EFV and RMP adds another layer of complexity that should be incorporated in pharmacogenomic algorithms to render drug response more predictable. The lecture will reflect also on pharmacogenomics of herbal medicines, and interaction with conventional drugs. There is a trend of important genes and their variants coming being prominent biomarkers for responses for commonly used drugs. The use of a wholistic approach in pharmacogenomics research translation that transcends disciplinary boundaries incorporating different “omics” ultimately leading to precision medicine.
Pharmacogenomics is relevant worldwide for modern therapeutics and yet needs further uptake in developing countries. There is paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and multiple drug treatments. To evaluate the role and impact of host underlying genetics on treatment response, different approaches are used depending on existing levels of understanding on the functional significance of genetic variants in question. This lecture showcases the work done pharmacogenomics research and how this has occurred in Africa and how “omics” is being leveraged. Our approach focuses on common disease conditions and commonly used medications including herbal medicinal plants.
We report on antiretroviral therapy and other treatments alter microRNA expression signatures and expression of drug-metabolizing enzyme genes, in vitro. These data point to several important clinical implications through changes in drug/drug interaction risks and achieving optimal therapeutics. Thus, differential expression of microRNAs after treatment with EFV and RMP adds another layer of complexity that should be incorporated in pharmacogenomic algorithms to render drug response more predictable. The lecture will reflect also on pharmacogenomics of herbal medicines, and interaction with conventional drugs. There is a trend of important genes and their variants coming being prominent biomarkers for responses for commonly used drugs. The use of a wholistic approach in pharmacogenomics research translation that transcends disciplinary boundaries incorporating different “omics” ultimately leading to precision medicine.
Collet Dandara
Professor Collet Dandara is currently serving as Deputy Dean of Postgraduate Education in the Faculty of Health Sciences, at the University of Cape Town. He is also a Director of the SAMRC/UCT Platform for Pharmacogenomics Research and Translation Unit (PREMED) and is a professor of human genomics. Collet Dandara is principal investigator of the pharmacogenomics & drug metabolism research group at the University of Cape Town. Collet is on the Executive Committee of the African Society for Human Genetics (AfSHG) as well as the African Pharmacogenomics Network (APN) and was Chair of the Southern African Society for Human Genetics (SASHG) (2021-2023). Professor Dandara serves on the Board of the Sydney Brenner Institute for Molecular Bioscience and served on the South African Medical Research Council (SAMRC) board from 2019 to 2022. Professor Dandara is a biomedical scientist with extensive experience in pharmacogenomics. Professor Dandara’s research covers the understanding of the pharmacogenomics of antiretroviral drugs and cardiovascular diseases including hypertension and cancer. Professor C Dandara is a current HUGO Executive Board Member. He is a Fellow of the Academy of Science of South Africa (ASSAf Fellow), a Fellow of the African Academy of Science (AAS-Fellow) and was part of the inaugural World Academy of Sciences (TWAS) Young Affiliate/Alumni (TYAN) Executive Committee (2016-2021). He has a track record of successful supervision of postgraduate students and has >160 publications in international peer-reviewed journals.
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This webinar is intended to provide education and updates of this evolving area to scientists and graduate students.
This webinar is organized by ISSX M&S and transporter FG jointly. It will cover from in vitro to the human PK prediction for transporter substrates with focus on the current challenge and possible solutions related to:
1) Critical In vitro methods /parameters needed for a reliable PBPK model predictions, data quality, gaps and how to overcome the limitations of in vitro system;
2) Key model structure and population parameters (including special populations) for transporter substrates - gaps in addressing multiple transporter involvement and interplay with enzymes;
3) Status of model validation for index substrates, applications in regulatory interaction and filing -challenges and future direction.
The webinar will include sufficient time for Q&A with invited field expert as panelists.
Xiaomin Liang
Xiaomin Liang, Ph.D., is a Senior Scientist II in the Department of Drug Metabolism at Gilead Sciences Inc. She obtained her B.S. degree in molecular toxicology from the University of California, Berkeley in 2011, and her Ph.D. degree in pharmaceutical sciences with a focus on membrane transporters, transporter-mediated drug disposition, and pharmacokinetics (PK) from the University of California, San Francisco in 2016. Following a brief fellowship at the Office of Clinical Pharmacology at the FDA, she joined Gilead in 2017. Her primary research interests are in the applications of transporter biology, in vitro methodologies, and mechanism-based PK/PBPK modeling to understand the ADME of compounds and translate preclinical data to predict human PK.
Ying-Hong Wang
Dr. Ying-Hong Wang is a senior reviewer in the Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences (OTS)/CDER. Prior to joining the FDA, she worked for 14 years at Merck, where she was responsible for preclinical and clinical development of numerous compounds in multiple therapeutic areas. She chaired the Quantitative Prediction of Drug Interaction Working Group and developed the internal guidelines for DDI prediction. Her modeling work on predicting and characterizing enzyme and transporter-mediated DDI and hepatic impairment contributed to the NDA approvals of grazoprevir/elbasvir and letermovir. Dr. Wang earned her Ph.D. from the Oregon Health Science University and completed her Clinical Pharmacology Fellowship training at the Indiana University-Purdue University Indianapolis. Her current research focuses on applications of PBPK modeling in CYP induction, transporter-mediated DDI, and hepatic impairment.
Kunal Taskar
Kunal Taskar, Ph.D., is currently working as Director, Global Head of PBPK Modelling at GSK. Kunal completed his doctorate more than a decade ago and postdoctoral research at Texas Tech University Health Sciences department, USA, in Quentin Smith’s lab with research focused on Neuropharmacokinetics and role of transporters in drug delivery across the blood-brain barrier (BBB).
Kunal’s experience and research focus include: PBPK modeling of small/large molecules and new modalities for PK and dose predictions, drug-drug interaction predictions and mechanistic understanding of the clinically occurring drug–drug interactions; and application of PBPK modeling in special populations including pediatrics, pregnancy, and organ impairment. His expertise also includes transporter mediated drug delivery and intracellular drug concentrations, especially the role of uptake and efflux transporters in drug pharmacokinetics-pharmacodynamics in disease and toxicology; novel transporters and role in drug disposition and use of endogenous probes and modeling for drug mediated transporter modulations.
Kunal is a member of American Society of Clinical Pharmacology and Therapeutics (ASCPT), International Society for the Study of Xenobiotics (ISSX) and the International Brain Barriers Society. Kunal is a member of several IQ consortiums including MIDD Pilot Program WG, Transporters, Induction PBPK and Pediatric PBPK. He is the founder member and Chair of the ASCPT QP PBPK Community. He received the 2014 AAPS Pharmaceutical Research Meritorious Manuscript Award for a manuscript that was published in the same journal in 2012. He has actively published and given invited talks and conducted workshops at international conferences.
Dr. Christine Bowman
Christine Bowman is a Principal Scientist in the Drug Metabolism and Pharmacokinetics Department at Genentech, Inc. She is a DMPK project lead for discovery and development projects and her research interests include improving in vitro to in vivo extrapolation with new in vitro methods and PBPK modeling, with a specific focus on transporters. Prior to joining Genentech, Christine received her PhD from the University of California, San Francisco under Dr. Leslie Benet.
Xiaoyan Chu
PhD
Dr. Xiaoyan Chu is a Senior Director in the Department of Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics at Merck & Co., Inc. in West Point, PA, USA. She obtained her PhD from the Department of Molecular Pharmacokinetics at the Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan. After completing her post-doctoral research at the Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan., she joined the Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism at Merck & Co., Inc. As the leader for the Transporter Science Group, her main responsibilities are to develop transporter related research and operational strategies to support Merck’s discovery and development portfolio, and to evaluate and establish new technologies and approaches to study the role of transporters in pharmacokinetics, efficacy, and toxicity of drugs. She has authored over 80 peer-reviewed research papers, book chapters, and has been invited to speak at over 40 national/international scientific conferences. She is the member of the International Transport Consortium (ITC) and serves as the Chair of the ISSX Transporter Focus Group from 2019 to 2022. She is also a member of the Editorial Board of Drug Metabolism & Disposition (DMD) and serves on the Industry Advisory Board at the College of Pharmacy & Pharmaceutical Sciences, Washington State University.
Bridget Morse
PhD
Dr. Bridget Morse is currently a Senior Director in PK/PD and scientific lead of Quantitative Clinical Pharmacology at Lilly Research Laboratories. She received her Pharm.D. from Butler University and her Ph.D. in Pharmaceutical Sciences from the University at Buffalo. Bridget has served in the pharmaceutical industry for 10 years as a subject matter expert in pharmacokinetics, transporters, clinical pharmacology and drug-drug interactions, particularly in the use of modeling for substrates of hepatic transporters. She chaired the IQ OATP1B Biomarkers Working Group from 2020-2023, is current Chair of the AAPS Drug Transporter Community and sits on the Editorial Advisory Board for the AAPS Journal. She has over 30 published journal articles and co-authors a recurring book chapter on drug transporters in Foye’s Principles of Medicinal Chemistry.
Manthena Varma
PhD
Dr. Manthena Varma, PhD is Research Fellow, at Pfizer Inc, Groton, CT. Dr. Varma received his B. Pharm. degree from the Kakatiya University, India, and an M.S. degree and PhD in Pharmaceutics, from the National Institute of Pharmaceutical Education and research (NIPER), Punjab, India. Later, Dr. Varma worked as a Post Doctoral Fellow at the Department of Pharmaceutics, University of Minnesota (Minneapolis). Dr. Varma holds an Adjunct faculty position in the Department of Pharmacy at the University of Rhode Island. His research focus include ADME/PK technologies and strategies in drug discovery and development, role of drug transporters and transporter-enzyme interplay (extended clearance) in ADME/PK, clinical pharmacokinetics and DDI predictions via mechanistic (PBPK) modeling. Varma supported preclinical and clinical development of several Pfizer compounds in the oncology, diabetes, and in NAFLD/obesity areas. He published about 150 original articles/reviews on a variety of ADME/PK topics.
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The workshop is neither trying to provide a 101 course on LC-MS proteomics nor attempts to focus on what is new in LC-MS proteomics techniques. Attendees need to have some background but not necessarily leading experts in the field. The consensus report from the previous ISSX Workshop held in 2018 (Prasad et al. 2019, Clinical Pharmacology and Therapeutics) is considered a background reading. The recent Symposium Repot from North American ISSX 2023 in Boston (Prasad et al 2024, Drug Metabolism Disposition, In Press) captures the content of lectures and workshop exercises. Hence, the event builds on what is known in the literature in relation to LC-MS proteomics and provides more practical guidance for those who are expanding their research activities in this area, such that they do not go through pitfalls and get to the end point faster.
In September 2018, ISSX held its very successful workshop on quantitative LC-MS proteomics as applied to drug development. The event was addressing a niche but growing utility area for LC-MS proteomics. Hence it involved small gathering of experts who debated unresolved issues and tried to provide a consensus on various elements of using quantitative LC-MS proteomics in translational DMPK/PD research.
The consensus, as well as issues which were not settled, appeared in an article that was published in Clinical Pharmacology and Therapeutics in 2019 (Prasad et al.). Since then, many groups have started to use LC-MS proteomics techniques and published on applications of this methodology. These reports have encouraged many other labs to consider getting engaged with this approach and integrate it into their research capabilities. However, there is currently no dedicated workshop or a course that takes the interested individual through the process of “setting Up an LC-MS lab for quantitative proteomics, conduct of experiments, analysis of raw data coming out of machine read out, and interpreting and applying them in translational pharmacology (whether PK or PD). This is addressed by the current workshop.
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This webinar is intended to share knowledge regarding development of a quantitative assay for siRNA using ddPCR.
Background: siRNA is a promising therapeutic modality highlighted by several US FDA approvals since 2018, with many more oligonucleotide assets in clinical development. To support siRNA discovery and development, robust and sensitive quantitative platforms for bioanalysis must be established to assess pharmacokinetic/pharmacodynamic relationships and toxicology. Droplet digital PCR offers improved sensitivity and throughput, as well as reduced susceptibility to matrix effects, compared with other analytical platforms. Methodology: The authors developed a stem-loop reverse transcription droplet digital PCR method to measure siRNA in mouse plasma and liver extract using bioanalytical method qualification guidelines. Conclusion: This newly developed assay has been demonstrated to be a superior alternative to other platforms, with the added benefit of greater sensitivity, with dynamic range from 390 to 400,000 copies/reaction and readiness for FDA investigational new drug-enabling applications.
Megan Turski
Megan Turski received her B.A. in Biology from University of Wisconsin-Madison. She has over 10 years of experience in bioanalysis working in the pharmaceutical industry. She began her career working in an FDA-regulated bioanalytical laboratory using LC-MS/MS and continued on to quantitative method validation and development for ligand binding assays and qPCR. She is currently a Scientist in the Drug Metabolism and Pharmacokinetics group at Takeda Pharmaceuticals in San Diego, CA. She primarily supports the bioanalysis for oligonucleotide drug candidates as well as the delivery platform development. Her current research focuses on developing PCR methods for oligonucleotides to determine pharmacokinetics and biodistribution of these drug candidates.
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The knowledge gained from this presentation will help scientists at all levels to learn about the latest developments in the structure elucidation of key drug transporters, that provide insights into how transporter alterations affect their function and may accelerate the discovery of more effective drugs to either target or evade transporters.
Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to move diverse substrates across the membrane. However, the plasticity of these proteins' ligand binding pockets, which allows them to bind a range of substrates, also poses a challenge for drug development. The structure, function, and transport mechanism of ATP-binding cassette (ABC)/solute carrier (SLC) transporters that are related to several diseases and multidrug resistance will be highlighted in this talk. ABC and SLC transporters play vital roles in clinical therapeutic outcomes. This talk will describe the current understanding of the structure of pharmacologically relevant transporters and how they interact with their ligands.
John Schuetz, Ph.D.
St. Jude Children's Research Hospital
John D. Schuetz received his Ph.D. from the Medical College of Virginia-Virginia/Virgina Commonwealth University with Robert Diasio (his lab identified the genetic basis of DPD deficiency); and conducted postdoctoral training with I. David Goldman (an SLC19A focused lab) and then wirh Philip Guzelian (identified Cyp3) cloned CYP3A5 and 7 at the same institution. He joined St. Jude Children’s Research Hospital as an Assistant Member (1992). He is a Member and former Vice Chair (2005-2022) of the Pharmaceutical Sciences Department. His lab reveals how transporters contribute to pathophysiology, drug response, and metabolism and has defined and functionally “deorphaned” transporters: ABCB6, ABCG2, and ABCC4 with over 175 articles in peerreviewed journals. He was nominated to membership in ASBMB. He is an Associate Editor for Pharmacological Reviews, Drug Resistance Updates, Drug Metabolism and Disposition and serves on the editorial boards of other journals. He was elected to the AAAS Electorate nominating committee and recently chair of the AAAS Pharmaceutical Sciences section S, elected Chair of the Toxicology Division of American Society for Pharmacology and Experimental Therapeutics (ASPET), Councilor and then ASPET’s President and nominated as an ASPET Fellow.
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This webinar is intended to update the ISSX community on some new development in peptide derivatization strategy that significantly improve the speed and accuracy of softspot and metabolite identification, which is essential for oral cyclic peptide discovery and development.
Part 1: 2-Pyridine Carboxaldehyde for Semi-Automated Soft Spot Identification in Cyclic Peptides: Cyclic peptides are an attractive option as therapeutics due to their ability to disrupt crucial protein-protein interactions and their flexibility in display type screening strategies, but they come with their own bioanalytical challenges in metabolite identification. Initial amide hydrolysis of a cyclic peptide results in a ring opening event in which the sequence is linearized. Unfortunately, the mass of the singly hydrolyzed sequence is the same (M + 18.0106 Da) irrespective of the initial site of hydrolysis, or soft spot. Soft spot identification at this point typically requires time-consuming manual interpretation of the tandem mass spectra, resulting in a substantial bottleneck in the hit to lead process. To overcome this, derivatization using 2-pyridine carboxaldehyde, which shows high selectivity for the alpha amine on the N-terminus, was employed. This strategy results in moderate- to high-efficiency derivatization with a unique mass tag and diagnostic ions that serve to highlight the first amino acid in the newly linearized peptide. The derivatization method and analytical strategy are demonstrated on a whole cell lysate digest, and the soft spot identification strategy is shown with two commercially available cyclic peptides: JB1 and somatostatin. Effective utilization of the automated sample preparation and interpretation of the resulting spectra shown here will serve to reduce the hit-to-lead time for generating promising proteolytically stable peptide candidates.
Part 2: Rapid and Definitive Identification of Cyclic Peptide Soft Spots by Isotope-Labeled Reductive Dimethylation and Mass Spectrometry Fragmentation: Cyclic peptides have been an emerging therapeutic modality over the past few decades. To identify drug candidates with sufficient proteolytic stability for oral administration, it is critical to pinpoint the amide bond hydrolysis sites, or soft spots, to better understand their metabolism and provide guidance on further structure optimization. However, the unambiguous characterization of cyclic peptide soft spots remains a significant challenge during early-stage discovery studies as amide bond hydrolysis forms a linearized isobaric sequence with addition of a water molecule regardless of the amide hydrolysis location. In this study, an innovative strategy was developed to enable rapid and definitive identification of cyclic peptide soft spots by isotope-labeled reductive dimethylation and mass spectrometry fragmentation. The dimethylated immonium ion with enhanced MS signal at a distinctive m/z in MS/MS fragmentation spectra reveals the N-terminal amino acid on a linearized peptide sequence definitively, and thus significantly simplifies the soft spot identification workflow. This approach has been evaluated to demonstrate the potential of isotope-labeled dimethylation to be a powerful analytical tool in cyclic peptide drug discovery and development.Yu Feng
Merck
Dr. Yu Feng is an associate principal scientist at Merck in the Nonclinical Drug Safety (NDS) department. Dr. Feng received his doctoral degree in pharmaceutical sciences from the University of Wisconsin-Madison under the supervision of Dr. Lingjun Li. Yu also holds Bachelor's degree in both organic chemistry and economics from Peking University, and completes MBA program at University of Illinois Urbana-Champaign. His research in Merck focuses on utilizing mass spectrometry techniques to advance the understanding mechanisms of toxicity and evaluate drug candidates. Dr. Feng has contributed significantly to the field, with more than 20 peer-reviewed publications and patents in biomolecule characterization, quantitative proteomics/glycomics and natural product synthesis.
Joe Cannon
Bristol Myers Squibb
Joe Cannon received his PhD in Biochemistry at the University of Maryland under Catherine Fenselau in 2012, and proceeded to consecutive post doctoral appointments at the University of Texas at Austin with Jennifer Brodbelt and Harvard Medical School with Wade Harper and Steve Gygi. He then joined Merck in 2018 and put his mass spectrometry skills to work with the biotransformation group and later as an ADME PI. He is currently an Associate Director of Biotransformation at Bristol Myers Squibb and supports company wide efforts in biotransformation, DMPK, and ADME across modalities.
Komal Kedia
Merck
Dr. Kedia received her Bachelors in Pharmaceutical Sciences from the Delhi University in New Delhi, India and her Ph.D. in Analytical Chemistry from Brigham Young University (BYU) under Dr. Steven Graves. Her work in Dr. Graves’s lab focused on identifying biomarkers (including proteins, peptides, lipids and other small molecules) of Preeclampsia, from placental tissue and blood to better understand the pathogenesis of this disorder. Following graduation, Dr. Kedia joined Pacific Northwest National Lab (PNNL) in Dr. Richard Smith’s group where she participated in multiple projects starting from biomarker discovery for several diseases, to method development for xenobiotics, specifically using LCMS and IMMS based approaches. She is currently an Associate Principal Scientist at Merck within PDMB group, where her responsibilities include supporting PK/PD studies and biomarker analysis across various internal programs. Additionally, Dr. Kedia is the project lead for the development and evaluation of different applications on a state-of-the-art, high-resolution ion mobility instrument based on SLIM technology, with the goal of providing program support across different modalities, especially for challenging analytes such as cyclic peptides and lipids.
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