The rockefeller university

Event Details

Type

Other Lectures and Symposia

Speaker(s)

9:00 a.m.: Shane Krska, Ph.D., Discovery Chemistry, Merck, Accelerating Drug Discovery Through Innovations in Catalysis and Industry-Academic Partnerships

9:20 a.m.: Martin Tomanik, Ph.D., Assistant Professor, Department of Chemistry, New York University, Radical-Triggered Functional Group Translocation and Total Synthesis of Talaromyolide D

9:40 a.m.: Danielle Schultz, Ph.D., Process Chemistry, Merck, Harnessing Collaboration and Enabling Technologies to Move Fast and Break Boundaries in Drug Discovery

10:00 a.m.: Jiankun Lyu, Ph.D., Assistant Professor and Head of Lab, The Rockefeller University, Virtual Screening of 100+-Billion-Molecule Libraries for Prospective Ligand Discovery

10:45 a.m.: Daniel Keedy, Ph.D., Associate Professor, City University of New York, High-Throughput Mapping of Ligandability in Allosteric Enzymes by Crystallographic Fragment Screening

11:05 a.m.: Yacob Gomez Llorente, Ph.D., and Sandra Gabelli, Ph.D, Structural Chemistry, Merck, Driving Pharmaceutical Breakthroughs through Structural Biology: Enlicitide a case study

11:25 a.m.: Chi-Min (Mimi) Ho, Ph.D., Assistant Professor, Department of Microbiology & Immunology, Columbia University, Molecular Basis of Malarial Host-Cell Invasion

11:45 a.m.: Kaavya Krishna Kumar, Ph.D., Assistant Professor of Pharmacology, Weill Cornell Medicine, Design of Safer Cannabinoid Receptor Ligands

12:05 p.m.: Michael Lazarus, Ph.D., Associate Professor of Pharmacological Sciences, the Icahn School of Medicine at Mount Sinai, Structural and Biochemical Studies on the Enigmatic YicC Family of RNases

2:00 p.m.: Heeseon An, Ph.D., Assistant Member, Chemical Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase1 Inhibitors for Targeting Mevalonate Metabolism in Cancer

2:20 p.m.: Christine Iok In Chio, Ph.D., Assistant Professor of Genetics & Development, Institute for Cancer Genetics, Columbia University Irving Medical Center, Redox Control of Systemic Metabolism in Cancer and Metabolic Disease

2:40 p.m.: Ralph Kleiner, Ph.D., Associate Professor of Chemistry, Princeton University, Illuminating RNA Biology with Metabolically Incorporated Ribonucleoside Probes

3:00 p.m.: Jennifer Hickey, Ph.D., Discover Chemistry, Oral Macrocyclic Peptide Inhibitors of IL-1β

Speaker bio(s)

9:00am Shane Krska

Accelerating Drug Discovery Through Innovations in Catalysis and Industry-Academic Partnerships

Rapid advances in human biology and the emergence of new therapeutic modalities such as macrocyclic peptides have generated exciting opportunities for drug discovery and synthetic chemistry. Modern synthetic methods have the potential to expedite the assembly of complex bioactive molecules; however, translating these fundamental breakthroughs into practical applications in medicinal chemistry requires close collaboration between industrial and academic partners. This presentation will utilize case studies to illustrate the diverse ways that modern synthetic methods, enabled by productive academic-industrial collaboration, can impact drug discovery.

9:20am Martin Tomanik

Radical-Triggered Functional Group Translocation and Total Synthesis of Talaromyolide D

Within the realm of chemoselective manipulations, site-selective functional group translocation via C–H functionalization presents an exciting opportunity to unlock new synthetic disconnections. I will highlight our development of a radical-triggered annulative alkene transposition cascade that enables a modular preparation of spirocyclic ethers. In the second part, I will discuss our synthetic strategy toward the highly oxidized meroterpenoid talaromyolide D. Our approach leverages efficient C–H disconnection logic to elaborate the polycyclic core of the target, along with several highly diastereoselective transformations, including an electrocatalytic sp²–sp³ cross-coupling.

9:40am Daniell Schultz

Harnessing Collaboration and Enabling Technologies to Move Fast and Break Boundaries in Drug Discovery

In this talk, I’ll be sharing how collaborations between industry and academia are essential for advancing synthetic chemistry to meet the increasingly complex demands of the therapeutic targets we aim to make.1 Brief case studies will illustrate how academic–industrial partnerships accelerate method development and translate discoveries into medicinal and process chemistry advances. Examples include direct sp3 C–H functionalization on pharmaceutically relevant scaffolds—approaches that, enabled by high throughput experimentation, expand late stage diversification and streamline access to target motifs.2,3 Lastly, recent advances will highlight the impact of non-canonical amino acids (ncAAs) on peptide drug discovery through late stage peptide functionalization and sustainable synthesis, and rapid access to peptide chemical matter via flow–solid phase peptide synthesis.4,5,6 The talk will conclude with practical lessons for building effective academic–industrial collaborations that deliver scientific impact and career development opportunities.

10:00am Jiankun Lyu

Virtual Screening of 100+-Billion-Molecule Libraries for Prospective Ligand Discovery

Ultra-large virtual libraries—now reaching into the hundreds of billions of compounds—offer unprecedented opportunities for ligand discovery. In this talk, I will first highlight recent successes using ultra-large libraries and explain why and how these libraries can guide ligand discovery. Second, I will present advances in scalable docking methods that enable efficient exploration of chemical space at the 100-billion–molecule scale, along with prospective tests showing how library size impacts hit rates and activity outcomes. Together, these perspectives illustrate both the promise and the ongoing challenges of integrating deep learning–based and physics-based approaches to accelerate structure-based drug discovery.

10:45am Daniel Keedy

High-Throughput Mapping of Ligandability in Allosteric Enzymes by Crystallographic Fragment Screening

Enzyme active sites are often highly conserved among homologs, resulting in low specificity for many orthosteric inhibitors. Allosteric sites present an attractive alternative, as they are often divergent in terms of the structural details of the binding pocket and/or the propensity to convey allosteric signals to the active site. As a result, they can enable specific modulation of a protein target, including either inhibition or activation. However, it remains a challenge to identify compounds targeting protein allosteric sites, much less to visualize at high resolution how many such compounds interact with the protein. Our group has used crystallographic small-molecule fragment screening to obtain thousands of X-ray datasets across two homologous phosphatase enzymes, resulting in hundreds of ligand-bound structures. We have analyzed the effects of data collection temperature on ligand poses, and have leveraged new X-ray data analysis algorithms to reveal dozens of additional hits. Our results reveal an array of surprising and useful interactions, including different types of unexpectedly covalent binders, new coupled ligand-protein conformations at an allosteric site, and buried ligands at a previously unresolved cryptic site. Altogether, our work points to the power of “statistical crystallography” as a framework for revealing how ligands reshape protein conformational landscapes to control function.

11:05am Yacob Gomez Llorente and Sandra Gabelli

Driving Pharmaceutical Breakthroughs through Structural Biology: Enlicitide a case study

Structural biology has evolved from a supporting discipline into a unifying engine that connects ideas to medicines. In this talk, we present Enlicitide, an orally bioavailable macrocyclic peptide inhibitor of PCSK9, as a case study illustrating how structural biology enables drug discovery and development from target validation to scalable manufacture. Structural insights were critical for target validation and modality selection, revealing a challenging protein–protein interaction best addressed by a peptide approach rather than small molecules. Throughout discovery, structure based drug design (SBDD) guided hit to lead progression and optimization, translating atomic level understanding into potency, selectivity, and developability. Beyond discovery, structural biology informed formulation strategies, solid form understanding, and process development and biocatalysis, enabling robust and scalable synthesis for clinical and commercial supply. Together, these efforts demonstrate how integrated structural biology accelerates decision making, bridges disciplines, and transforms fundamental molecular insight into innovative medicines that address major unmet medical needs.

11:25am Chi-Min (Mimi) 

Molecular Basis of Malarial Host-Cell Invasion

Research in the Ho Lab focuses on understanding how malaria parasites co-opt and remodel membranes at the host-pathogen interface. The complexity and breadth of its host-cell remodeling machinery make the malaria parasite Plasmodium falciparum a rich and exciting system for the study of host-pathogen interfaces. Unfortunately, many of the molecular mechanisms underlying this parasite’s ability to hijack human red blood cells remain enigmatic, as much of the P. falciparum proteome has proven recalcitrant to structural and biochemical characterization using traditional recombinant approaches. To address this major knowledge gap, the Ho Lab develops and applies novel approaches for endogenous structure determination from malaria parasites, combining cutting-edge CryoEM and in situ CryoET with biophysics and parasite genetics to overcome longstanding barriers to high resolution structural study in malaria parasites.

11:45am Kaavya Krishna Kumar

Design of Safer Cannabinoid Receptor Ligands

The CB1 cannabinoid receptor is a well-established target for pain management, but its activation is often linked to severe psychoactive side effects. In this talk, I will describe our recent efforts to dissect CB1 activation at the structural and biophysical level, and how we used these insights to re-engineer the synthetic cannabinoid MDMB-Fubinaca. By identifying a cryptic binding pocket and applying computational and structure-guided design, we developed new ligands with biased signaling and restricted CNS penetration. This work illustrates how fundamental mechanistic insights can guide the development of safer GPCR-targeted therapeutics.

12:05pm Michael Lazarus

Structural and Biochemical Studies on the Enigmatic YicC Family of RNases

We recently discovered a novel family of RNases widely conserved across bacteria that is completely distinct from known RNases. Using cryo-EM and biochemical techniques, we are beginning to understand how the prototypical E. coli family member YicC functions. Questions still remain about its purpose in bacteria and its exact mechanism, but our latest work is shedding light on these questions.

1:30 - 2:00pm Student Flash Talks 

2:00pm Heeseon An

Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase1 Inhibitors for Targeting Mevalonate Metabolism in Cancer

Comprehensive target validation remains a significant bottleneck in chemical probe development, particularly for covalent inhibitors, where off-target reactivity can lead to toxicity. Using HMG-CoA synthase 1 (HMGCS1), an underexplored gatekeeper enzyme in the mevalonate pathway, we demonstrate how integrating orthogonal chemoproteomic methods can provide unbiased, comprehensive insights into the on- and off-target profiles of covalent inhibitors. Our study specifically highlights the limitations of traditional enrichment proteomics in distinguishing high-occupancy binders from low-occupancy binders, and proposes a solution through a complementary scavenging proteomics approach that analyzes de-enriched fractions, providing target engagement ratios across the proteome. This framework facilitated the development of CNP7, a cyanopyrrolidine that covalently modifies HMGCS1's catalytic cysteine with remarkable selectivity, as assessed by comprehensive chemoproteomics. A 2.29 Å cryo-EM structure reveals how CNP7 engages the catalytic cysteine within HMGCS1’s hydrophobic pocket. CNP7 treatment decreases HMG-CoA levels and induces global protein deprenylation within four hours. Notably, CNP7 exhibits cell line-specific anti-cancer activity patterns that differ from statins, suggesting possible pathway node-specific vulnerabilities. Together, our study offers valuable chemical tools to modulate HMGCS1 activity and presents a framework for rigorous characterization of covalent inhibitors in chemical biology and drug development.

2:20pm Christine Iok In Chio

Redox Control of Systemic Metabolism in Cancer and Metabolic Disease

Disruption of iron metabolism is a hallmark of cancer and can profoundly reshape redox homeostasis. We have identified an iron-dependent mechanism that links redox regulation to systemic metabolic remodeling through methionine oxidation. Specifically, we find that methionine sulfoxide reductase A (MSRA) is regulated by iron and functions to control a network of methionine redox modifications in metabolic proteins. In pancreatic cancer, this pathway is activated in peripheral tissues and drives adipose remodeling associated with cancer cachexia. Using chemoproteomic approaches, we show that tumor-bearing hosts exhibit tissue-specific changes in methionine oxidation, revealing a coordinated redox program that extends beyond the tumor itself. Functionally, this axis integrates iron availability with signaling pathways that control lipid metabolism and energy expenditure. Interestingly, elements of this pathway are also engaged in non-malignant metabolic contexts, including obesity, suggesting a broader role for methionine redox regulation in systemic metabolism. Together, these findings define an iron-MSRA-methionine redox axis as a mechanism by which cancer rewires host metabolism and highlight its potential as a target for therapeutic intervention.

2:40pm Ralph Kleiner

Illuminating RNA Biology with Metabolically Incorporated Ribonucleoside Probes

RNA plays a central role in biological processes and characterizing the regulatory mechanisms governing its behavior can reveal fundamental insights into gene expression programs in normal and disease contexts. Our lab has developed general approaches based upon RNA metabolic labeling with artificial ribonucleoside probes to study RNA-associated processes at transcriptome-wide scale in live cells and organisms. In particular, I will discuss RNA-mediated activity-based protein profiling (RNABPP), a chemoproteomic strategy to profile RNA modifying enzymes in their native context. We have applied RNABPP method with 5-halopyrimidine nucleosides in bacteria and mammalian cells to enable the discovery and characterization of novel RNA modifying enzymes. Taken together, our work provides general strategies for interrogating RNA regulation and reveals the presence of novel mechanisms controlling RNA function in biological systems.

3:00pm Jennifer Hickey

Oral Macrocyclic Peptide Inhibitors of IL-1β

Interleukin 1β (IL 1β) is a central driver of inflammation and a clinically validated target in atherosclerotic cardiovascular disease, as established by the CANTOS trial with canakinumab. However, the therapeutic impact of IL 1β blockade has been limited by the need for injectable biologics with prolonged systemic exposure and associated safety considerations. In this presentation, we will describe the discovery of a new class of orally delivered macrocyclic peptide inhibitors of IL 1β that replicate the anti inflammatory pharmacology of canakinumab while enabling improved drug like properties. The presentation will highlight how mRNA display, structural biology, and rational peptide design were integrated to overcome key challenges in potency, stability, and pharmacokinetics, culminating in robust pre-clinical in vivo efficacy.

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