Pharmaceutical Sciences Seminar Series

Mondays, 12 – 1 p.m.
Location: Varies

For more information contact: adekerme@uci.edu

Spring 2025

31 MARCH 2025: TBD

07 APRIL 2025: TBD

14 APRIL 2025: TBD

21 APRIL 2025: TBD

28 APRIL 2025: TBD

05 APRIL 2025: TBD

12 MAY 2025: TBD

19 MAY 2025: TBD

02 JUNE 2025: TBD

Winter 2025

24 FEBRUARY 2025: TBD

03 MARCH 2025: TBD

10 MARCH 2025: TBD

17 MARCH 2025: TBD

Fall 2024

30 SEPTEMBER 2024: TBD

07 OCTOBER 2024: Jason Gestwicki, UCSF

14 OCTOBER 2024: Nicoleta Tsvetanova, Duke University

21 OCTOBER 2024: TBD

28 OCTOBER 2024: TBD

04 NOVEMBER 2024: TBD

18 NOVEMBER 2024: TBD

02 DECEMBER 2024: TBD

09 DECEMBER 2024: TBD

Spring 2024

01 APRIL 2024: Mathew Blurton-Jones, UCI

“Talk Title TBD”

08 APRIL 2024: Luke Lairson, TSRI

“Talk Title TBD”

15 APRIL 2024: Mahtab Jafari, UCI

“Talk Title TBD”

22 APRIL 2024: Gloria Brar, Berkeley

“Talk Title TBD”

29 APRIL 2024: Roshanak Irannejad, UCSF

“Talk Title TBD”

06 MAY 2024: Nicholas Ingolia, Berkeley

“Talk Title TBD”

13 MAY 2024: Michael Wendt, University of Iowa

“Talk Title TBD”

03 JUNE 2024: Mia Huang, TSRI

“Talk Title TBD”

Winter 2024

24 JANUARY 2024: Matthew Disney, UC Scripps

“Design of Small Molecules Targeting RNA Structure”

26 FEBRUARY 2024: Carol Mulrooney, GSK

“Expanding the Chemical Space of DNA-Encoded Libraries in Two and Three Dimensions”

04 MARCH 2024: Jennifer Petter, Arrakis

“Expanding the Chemical Space of DNA-Encoded Libraries in Two and Three Dimensions”

18 MARCH 2024: Ying Zhang, X-Chem

“DEL Platform For Early Drug Discovery”

Fall 2023

09 OCTOBER 2023: Ben Morehouse, UCI School of Biological Sciences

Title: Cyclic nucleotide signaling in bacterial antiviral immunity


Summary: The constant threat of attack by pathogens drives the evolution and diversification of immunological defense mechanisms that provide living things with protection from infection. Recently, cyclic ribonucleotide signaling molecules have emerged as critical players controlling specialized antiviral pathways in humans and in newly discovered microbial antiphage defense systems. There has also been a paradigm shift in the field with the realization that many of the innate immune defense systems observed in humans stem from ancient, conserved phage defense pathways encoded in prokaryotic genomes. In this seminar I will introduce some of these recently uncovered immune defense strategies employed by bacteria including novel enzymes and receptors that regulate cell growth arrest or death to halt viral infection. There will be a particular emphasis on the connections these defense systems have to our own innate immune system.

16 OCTOBER 2023: Galia Debelouchina, University of California, San Diego

Title: Molecular basis of heterochromatin formation and regulation


Summary: Heterochromatin protein 1a (HP1a) plays a central role in the organization of nuclear content by coordinating a complex network of events that leads to the formation of genetically silent heterochromatin neighborhoods. It is believed that this process involves the phase separation of HP1a into liquid droplet compartments. Capturing the molecular interactions that drive heterochromatin formation has been difficult due to the heterogeneous nature of chromatin and HP1a, both of which contain rigid and dynamic components. To understand this system, we have used a biophysical toolbox that includes solution and solid-state NMR spectroscopy, fluorescence imaging, and molecular dynamics simulations. These approaches have allowed us to describe the interactions that drive the phase separation of HP1a, understand how HP1a interacts with chromatin, and ellucidate how these activities can be regulated by HP1a binding partners, thus building a comprehensive molecular view of this elusive biological process.

30 OCTOBER 2023: Enver Izgu, Rutgers University

Title: Synthetic Approaches that Expand the Functionality of Nucleic Acids and Lipids


Summary: Our lab is inspired by the potential of nucleic acids and lipids as biotechnology tools. Recently, we developed a small-molecule approach that enables a known RNA aptamer to detect new and non-fluorescent inorganic targets, without the need of SELEX1. We integrated this approach to E. coli, thereby generating cell-based biosensors. We also developed split-DNA-aptamers detecting cancer-associated miRNAs2.These platforms can use xeno-nucleic acids, among which we study NP-DNA, a nuclease resistant RNA mimic. Reverse transcriptases recognize NP-DNA as a template 3, and NP-DNA can be synthesized by engineered polymerases4.

Lipids are another class of molecules we design 5-7. One particular phospholipid allows for the detection of iNOS-dependent nitrative stress within subcellular lipid membranes (mainly ER) and the lung lining in murine models of ex vivo and in vivo acute lung injury 7.

My seminar will describe the structure- and reactivity-guided design principles and biological implementations of these molecular tools from a chemist’s perspective.

06 NOVEMBER 2023: Danielle L. Schmitt, University of California, Los Angeles

Title: Illuminating Compartmentalized Regulation of Cellular Metabolism


Summary: Metabolism is a central process to life, and the precise spatiotemporal control over metabolism is critical for proper cellular and organismal function. The Schmitt Lab is interested in understanding how metabolism is spatiotemporally regulated within the cell at distinct subcellular locations, and how this regulation is perturbed in metabolic diseases. Our work has two main focuses: to (1) understand how the signaling networks regulating metabolism are spatiotemporally localized and the downstream effects of localized activity; and (2) to study compartmentalized metabolic flux in health and disease. Our approach to understanding compartmentalized metabolic regulation is to develop genetically encoded fluorescent protein-based biosensors to detect and measure changes in cellular activity with high spatial and temporal resolution. In this talk I will describe ongoing efforts within the lab to study metabolic regulatory networks and develop new tools for imaging metabolism.

13 NOVEMBER 2023: Ilia A. Droujinine, Scripps

Title: Untangling the interorgan communication network


Summary: The secreted proteome represents a poorly-characterized interorgan communication network, which is central in the etiology of various metabolic disorders including obesity and type 2 diabetes. Despite this, the composition and activity of interorgan communication networks and their impact on disease remain poorly defined, as it has historically been difficult to identify the secreted proteins due to their low abundance and lack of information on their organ(s) of origin and destination. To address this, we established in mice a conditional BirA*G3 engineered biotin ligase system that generally labels secreted proteins within the endoplasmic reticulum of one organ, allowing identification of proteins that traffic to distal organs using affinity enrichment and quantitative mass spectrometry. Using this approach, we identified hundreds of proteins trafficking from intestinal epithelium to distal organs, including the known low-abundance (~pg/mL) hormones such as GLP-1. Furthermore, we identified and characterized a novel diet- and obesity-regulated intestinal-secreted protein specifically acting on subcutaneous white adipose tissue. Our methods are widely applicable to proteins secreted from other organs, establishing a new strategy to broadly define the whole-body interorgan communication networks. Our lab continues to develop and apply approaches to decipher the secreted ligands involved in communication between multiple organs and in various diseases.

20 NOVEMBER 2023: Charlie Fehl, Wayne State University

Title: Chemical tools to capture and control hexosamine sugar signaling in hyperglycemic disease


Summary: All cells use sugar, but a consequence of unbalanced sugar usage is disease through hexosamine sugar signaling pathways including glucosamines. To precisely define the roles of hexosamine sugar-driven effects, the Fehl Group designs chemical tools sensitive for live-cell applications, for example our light-controlled photosugars and our cell compartment-specific “GlycoID” labeling strategy. We apply chemical biology tools at the interface of metabolism disease and cancer pathways to discover new roles for glucose-driven events in cells and disease. A key target area is determining the mechanisms and potential treatment strategies for cancers that have elevated risk in patients with hyperglycemia.

27 NOVEMBER 2023: Fleur M. Ferguson, University of California, San Diego

Title: Interrogating the Druggable Proteome with Proximity Pharmacology


Summary: Unbiased chemical biology strategies for direct readout of protein interactome remodelling by small molecules provide advantages over target-focused approaches, including the ability to detect previously unknown targets, and the inclusion of chemical off-compete controls leading to high-confidence identifications. We describe the BioTAC system, a small-molecule guided proximity labelling platform, to rapidly identify both direct and complexed small molecule binding proteins. The BioTAC system overcomes a limitation of current approaches, and supports identification of both inhibitor bound and molecular glue bound complexes.

Spring 2023

05 APRIL 2023: Reginald McNulty, UCI School of Biological Sciences

Title

A Novel Mechanism of NLRP3 Inflammasome activation

Summary

This project aims at advancing our knowledge, from a molecular basis, of macromolecular complexes involved in the innate immune response. The NLRP3 inflammasome has been identified as a key immune sensor for tissue damage. Although NLRP3 inflammasome assembly/activation leads to the production of inflammatory messengers (called cytokines) that alert the host immune system to initiate inflammatory responses, its dysregulation often results in overt diseases due to uncontrolled inflammation. Unfortunately, exposure to a number of natural and manmade toxicants induce NLRP3 inflammasome activation that in turn initiates an undesirable inflammatory response, thereby causing pathologies. Activating molecules trigger mitochondrial damage and subsequent release of mitochondrial contents that somehow signal the activation of NLRP3 inflammasome. In this project, we seek to characterize inflammasome macromolecular assembly structures in the presence of direct binding ligands.

12 APRIL 2023: Matthew Griffin, UCI Department of Chemistry

Title

Sensing a pattern: Modulating host function via microbial glycans

Summary

Microorganisms that live in and on our bodies—our microbiota—have been associated with numerous states of human health and disease. However, very few causal factors have been discovered to explain these initial, sequencing-driven correlations. In this talk, I will describe our lab’s interest in determining exact molecular mechanisms that allow specific microbes to initiate host immunity through the generation of glycan-containing molecular patterns. I will first summarize my recent postdoctoral work, where we found that unique secreted enzymes from the bacterial genus Enterococcus were able to degrade cell wall peptidoglycan (PG). Increased PG degrading activity in the gut yielded muropeptides that activated a canonical innate immune signaling pathway, ultimately increasing adaptive anti-tumor immunity and potentiating checkpoint inhibitor blockade in murine models of cancer. I will then highlight recent work in my independent lab to identify new families of PG hydrolytic enzymes in other correlated microorganisms and to apply this enzymatic activity as a new biotherapeutic platform. Together, these efforts underscore our lab’s goal to identify conserved functional mechanisms that transcend phylogeny and explain the myriad, disparate associations between microbiota.

19 APRIL 2023: Christopher Parker, Then Scripps Research Institute

Title

Chemoproteomic Ligand and Target Discovery in Cells

Summary

Advances in DNA sequencing and editing technologies have dramatically expanded our molecular understanding of human diseases and have yielded unparalleled insight into protein function. However, many disease-relevant genes encode proteins that are poorly characterized and/or are considered “undruggable”, hindering our understanding of disease mechanisms and the translation of this knowledge into new therapies. Chemical probes offer a valuable way to directly interrogate the function and disease-relevance of proteins and can also serve as valuable leads for drug development, yet most proteins in the human proteome lack small-molecule ligands that can serve as probes. More generally, the boundaries, if any, on the ligandability, and therefore potential druggability, across native proteomes remains poorly understood. In this seminar, I will describe our lab’s efforts to develop powerful chemical proteomic strategies to broadly map ligandable proteins directly in cells, and how this information can be advanced into useful chemical probes for proteins that play critical roles in human health and disease.

03 MAY 2023: Mia Huang, The Scripps Research Institute

Title

Pharmaceutical Sciences Seminar: Taming Glycoconjguate Structure and Interactions in development and Disease

Summary

Protein glycoconjugates, protein products modified with glycan post-translational modifications, are often considered untamable biomolecules. A single glycoconjugate exists as a mixture of heterogeneous unique protein glycoforms in living cells, resulting in innumerable possible interactions with glycan-binding proteins. These interactions play key roles in orchestrating physiology and disease. However, current approaches to describe protein glycoconjugates and their interactions are limited, restraining our understanding of the consequent important and often critical functions. Using innovative interdisciplinary approaches rooted in chemical biology and high-resolution mass spectrometry, I will outline our efforts to dismantle the complexity of protein glycoconjugates. These endeavors include the fabrication of defined proteoglycans that control cancer cell adhesion on matrices and the elucidation of the proteome-wide interactions of glycan-binding proteins in liver fibrosis and myogenesis, as well as the development of synthetic small molecules that differentially engage various protein glycoforms.

10 MAY 2023: Yun Ding, GlaxoSmithKline (GSK)

Title

Advances in DNA-Encoded Library Technology (ELT): From on-DNA Chemistry to Preclinical Candidate

Summary

DNA-encoded library technology has been proven to be a powerful tool to identify small molecule ligands for both target validation and medicinal chemistry progress. It allows the construction and screening of combinatorial libraries with unprecedented size and provides access to much broader chemical diversity, thus facilitating the discovery of ligands to different biological targets. In this seminar, I will discuss the recent advances in on-DNA reaction development, with a focus on transition metal catalyzed coupling, heterocycle formation, macrocyclization, photoredox chemistry and enzyme catalyzed reactions. A case study highlighting the successful application of DEL platform for the identification of preclinical candidate will also be presented.

24 MAY 2023: Roberto Zoncu, Berkeley

Title

The Lysosome in Nutrient Sensing and Cellular Growth Control

Summary

The lysosome plays a central role in cellular homeostasis through its participation in autophagy and its physical and functional association with the master growth regulator, mechanistic target of rapamycin complex 1 (mTORC1) kinase. mTORC1 integrates signals from nutrients, hormones and energy to control the balance between cellular growth and repair programs. Nutrients, including cholesterol, drive the localization of mTORC1 to the lysosomal membrane, where mTORC1 becomes competent to phosphorylate its downstream targets. Cholesterol sensing by mTORC1 occurs upstream of the heterodimeric Rag guanosine triphosphatases (GTPases) and is negatively regulated by the cholesterol exporter, Niemann-Pick C1 (NPC1) protein. In NPC1-deleted cells, mTORC1 becomes hyperactivated, leading to disruption of autophagy and mitochondrial function. Despite these advances, our understanding of how cholesterol regulates mTORC1 remains limited. We lack a complete knowledge of the cholesterol-regulated proteins that translate lysosomal cholesterol levels to modulation of the Rag GTPases. Moreover, we do not know how cholesterol-dependent mTORC1 activation results in regulation of specific downstream metabolic programs, and how disruption of this pathway contributes to NPC pathogenesis. I will present our recent effort to unravel lysosomal cholesterol sensing through a combination of organelle proteomics, bioinformatic analysis and functional assays. In particular, I will present evidence for a lysosome-based cholesterol sensors, termed LYCHOS, which enables mTORC1 activation via cholesterol-dependent regulation of the Rag GTPase nucleotide state. Moreover, I will discuss ongoing work leveraging functional genomics to identify new pathways for cellular quality control with significance to NPC pathogenesis.

31 MAY 2023: Jon Long, Stanford

Title

Molecular effectors of physical activity

Summary

Despite the profound benefits of physical activity for human health and longevity, the molecular effectors of exercise remain poorly defined. Here we will discuss our past and ongoing work on blood-borne exercise-inducible molecules, their downstream pathways, and physiologic effects. Key to our approach is the use of mass spectrometry-based metabolomics and proteomics, which we combine with genetics and biochemical approaches in mice and humans. Our studies uncover potential translational opportunities for pharmacological capture of the benefits of physical activity for human health.

Winter 2023

05 JAN 2023: Dan Gil, PhD, Siege Pharmaceuticals

Title

Rational Drug Design to Optimize Selectivity

Summary

Strategic drug design is critical for achieving both potent interactions with the target and exposure in the appropriate organs and tissues. This medicinal chemistry tutorial will cover two case studies in molecular design: 1) targeting the muscarinic receptor in the brain as a potential therapeutic strategy for Alzheimer’s Disease, and 2) targeting the nutrient sensing tumor suppressor PP2A in cancer. Dr. Gil was formerly the Vice President, Research Technologies and Portfolio at Allergan and is now a serial entrepreneur and venture capital consultant leading several drug discovery/biotechnology start-up companies.

11 JAN 2023: Stephen Hanessian, PhD, UCI Distinguished Professor

Title

“Academic−Industrial Research Collaboration: Toward the Consilience of Two Solitudes”

Abstract

Living in a symbiotic yet non-invasive coexistence, the academic community and the pharmaceutical industry have strived, each in their own way, to develop modern-day medicines that benefit humankind today. The subject is presented from a personal perspective focusing on past and present successful research collaborations with pharmaceutical and biotechnology companies worldwide.

18 JAN 2023: Punit Seth, PhD, Alnylam Pharmaceuticals

Title

“Delivering On The Promise of RNAi Therapeutics”

Abstract

RNA targeted therapeutics represent the third bonafide platform for drug discovery within the pharmaceutical industry. At least 14 RNA-based medicines have been approved by regulatory agencies with several hundred additional agents in early to late-stage clinical development. In this presentation, we will discuss advances made in the design and delivery of RNAi therapeutics and the future prospects for this class of revolutionary medicines. 

25 JAN 2023: Dr. Dean Brown, SVP and Head of Discovery Sciences and Jnana Therapeutics

 Title

“Analysis and implications for the future of drug discovery-FDA-approved drugs 2010-2020”

Abstract

A total of 378 novel drugs and 27 biosimilars approved by the FDA between 2010-2019 were evaluated according to approval numbers by year, therapeutic areas, modalities, route of administration, first-in-class designation, approval times, and expedited review categories. From this review, oncology remains the top therapy area (25%), followed by infection (15%) and central nervous system (11%). Regulatory incentives have been effective as evidenced by an increase in orphan drugs as well as antibacterial drugs approved under the GAIN act. Clinical development times may be increasing, perhaps as a result of the increase in orphan drug indications. Small molecules continue to mostly adhere to “Rule of 5” (Ro5) parameters, but innovation in new modalities israpidly progressing with approvals for antisense oligonucleotides (ASO), smallinterfering RNA (siRNAs), and antibody-directed conjugates (ADC). Finally, novel targets and scientific breakthroughs that address areas of unmet clinical need are discussed in detail.

8 FEB 2023: Marie Malone, Nurix Therapeutics

 Title

“Utilizing DEL as a Primary Discovery Engine for Targeted Protein Modulation (TPM)”

Abstract

Nurix’s DELigase platform is deployed to identify small molecules that can either increase or decrease protein levels (targeted protein modulation, TPM) and relies on two underlying capabilities: Nurix’s expertise with E3 ligases and DNA-encoded libraries (DELs) of small molecules. DELs are uniquely suited to TPM applications. They are designed to target difficult to drug targets and for rapid hit follow up and optimization. The scalability of DEL screening enables the assembly of a comprehensive database of screening results from a broad exploration of target space that is key to navigating through the DEL data and identifying chemotypes with desirable profiles. Combining traditional and computationally driven DEL follow-up enables identification of a higher number of binders in desirable chemical space. This maximizes the diversity of confirmed hits and enables rapid progression of both inhibitor and degrader drug development campaigns.

22 FEB 2023: Dr. John P. Maxwell, SVP, Tango Therapeutics

Title

“Pitfalls and barriers in small molecule drug discovery”

Abstract

Behind every successful ending to a drug discovery story is a successful beginning. In this tutorial we will review the early stages of small molecule drug discovery, discussing some of the many ways to approach the problem, and some of the many ways to be misled. This will not be positioned as “academic vs industrial” but is intended to bring awareness to the less publicly visible aspects of this stage of drug discovery. Additionally, we will introduce some basic concepts in SAR and how chemists and biologists together can contribute to its development.

1 MARCH 2023: Daniel Holland- Moritz, Scientist, Merck

Title

“Microfluidic Droplet Sorting with Mass Spectrometry Enables Rapid Directed Evolution”

Abstract

Directed evolution of enzymes for biocatalysis requires screening thousands of variants to identify those capable of mediating a desired chemical transformation. Droplet microfluidics offers significant advantages for enzyme screening by scaling assays down into nanoliter scale microdroplets, but to date, these microfluidic reactions have only been possible to screen using a limited array of fluorogenic assays. In this work, we carry out the entire protein engineering workflow in nanoliter droplets, and apply Mass Activated Droplet Sorting (MADS) to overcome this analytical challenge and sort droplets via direct detection using mass spectrometry. Our workflow employs less than 3 mL of reagents to express and assay thousands of enzyme variants. The process is completed in three days by a single scientist, representing materials and cost reductions of more than 90% and a hundred-fold increase in analytical throughput. MADS-enabled protein engineering represents a significant step forward in high throughput screening for directed evolution.

8 MARCH 2023: Cyrus Khojasteh, Sr. Director, Genentech

Title

“Solving biotransformation challenges in the new era”

Abstract

Drug metabolism is one of the major mechanisms of drug clearance from the body. This includes a wide array of enzymes that cover oxidation, reduction, hydrolysis, and conjugation. Over the past decades, extensive research focus on cytochrome P450 enzymes has allowed for a better understanding of the role of these enzymes in determining the ADME properties of drugs. Though P450s for the most part still play a significant role in drug metabolism for small molecules, understanding other drug-metabolizing enzymes is becoming important. This requires biotransformation researchers with a broader knowledge of the drug-metabolizing enzymes and here we explore the how with examples.