Speakers
Keynote Speakers​​​​​​​
Prof. Christina M. Woo | Harvard University
Christina M. Woo is a Professor in the Department of Chemistry and Chemical Biology at Harvard University, and an associate member of the Broad Institute. Research in the Woo lab aims to define and exploit the contribution from protein modifications in cells using the tools of chemical biology. Prior to Harvard, Christina obtained a BA from Wellesley College (2008), PhD with Professor Seth Herzon in Chemistry from Yale University (2013), and completed postdoctoral studies with Professor Carolyn Bertozzi at the University of California, Berkeley and Stanford University in Chemical Biology (2016). Her research program has been recognized by the Cope Scholar Award, David Gin Young Investigator Award, Camille-Dreyfus Teacher-Scholar Award, Sloan Research Foundation, NSF CAREER, Amgen Young Investigator Award, Bayer Early Excellence in Science Award, and the Ono Pharma Foundation Breakthrough Science Award.
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Dr. Jeffrey W. Johannes | AstraZeneca
Dr. Jeffrey W. Johannes is Director of Oncology Medicinal Chemistry at AstraZeneca in Waltham, MA, where he leads drug discovery teams developing AstraZeneca’s next-generation oncology medicines and manages a group of nine medicinal chemists. He earned a B.S. in chemistry from Harvey Mudd College, where he explored synthetic transformations of the fullerene C₆₀. He then joined the laboratory of Professor Yoshito Kishi at Harvard University, completing a Ph.D. for his work on the total synthesis of gymnodimine and remaining for an additional year as a postdoctoral fellow before joining AstraZeneca in 2006. For the past nineteen years Jeff has worked on a broad range of oncology targets, spanning both lead-generation and lead-optimization phases of drug discovery. In the cell-death space he was part of the team that delivered the Mcl-1 clinical candidate AZD5991. He has worked extensively on kinase projects, including the discovery of AstraZeneca’s selective CDK2 inhibitor AZD8421. Within the field of PARP inhibition, Jeff led the chemistry effort on tankyrase inhibitors for the Wnt pathway, culminating in the identification of the selective tankyrase inhibitor AZ6102. He also led the chemistry teams that discovered AstraZeneca’s second-generation, PARP1-selective inhibitor AZD5305 (saruparib) and the CNS-penetrant, PARP1-selective inhibitor AZD9574.
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Student/Postdoc Speakers
Dr. Brett Akana-Schneider | Derosa Group, Boston University
Electrochemical Azolation of Electron-rich Fluoroarenes: A Controlled Redox Chain Unlocks C–N Bond-forming e-SNAr
Nucleophilic aromatic substitution (SNAr) reactions are critical methods for forming C–N bonds in synthetic campaigns, but limitations in electrophile electronics restrict access to a large portion of chemical space. Photochemical oxidation of fluoroarenes has emerged as an attractive strategy to activate fluoroarenes towards nucleophilic addition, but back-electron transfer to solution-phase, reduced photocatalysts limit the scope and efficiency of these methods. We have developed an electrochemical strategy to overcome this obstacle by spatially separating redox events at electrode surfaces, extending the lifetime of the activated electrophile and enabling the azolation of electron-rich alkoxyfluoroarenes. Through stabilization of the oxidized product with voltage control and HFIP solvent, this method prevents product inhibition or decomposition, enabling an uphill redox chain mechanism. A wide range of electron-rich fluoroarenes and azoles are tolerated—including those with orthogonal functional group handles. Further, the redox catalytic nature of this e-SNAr reaction enables energy and mass efficient syntheses and facile scaling in a simple batch setup.
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Richard S. Morales | Scientist, Automated Chemical Synthesis, AstraZeneca
Building Robust Automated Workflows for Reaction Optimization and Multi-Parallel Synthesis at AstraZeneca
​Within the Adaptive Chemistry Team (ACT) in Oncology Targeted Discovery Chemistry at AstraZeneca, we are actively utilizing automation to enable High-Throughput Chemistry (HTC) workflows with the goal of accelerating all stages of early drug discovery from lead identification to candidate drug selection. This presentation showcases our strategic deployment of automated platforms for synthetic chemistry to support early-stage medicinal chemistry, emphasizing the importance of enabling rapid structure–activity relationship generation, scalable route development, and sustainable practices. Through case studies highlighting different automated workflows for reaction and non-reaction optimization, we demonstrate how iterative High-Throughput Experimentation (HTE) can enable the rapid identification of robust reaction conditions, yield improvement, and often reduced environmental impact. This work has resulted in significant improvements to library success rates and throughput, as well as acceleration of project timelines through dedicated synthetic support, underscoring the transformative potential of automation driven synthesis in modern pharmaceutical research.
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Shawn Ng | Hoveyda Group, Boston College
Catalytic Prenyl Conjugate Additions for Synthesis of Enantiomerically Enriched PPAPs
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of >400 natural products with a broad spectrum of bioactivity. They are found in nature in either enantiomeric form and contain a densely substituted core structure with multiple prenyl groups. We present a scalable, regio-, site-, and enantioselective catalytic method for synthesis of cyclic β-prenyl ketones, compounds that can be used for efficient syntheses of many PPAPs in high enantiomeric purity. The transformation is a prenyl conjugate addition to cyclic β-ketoesters promoted by a readily accessible chiral copper catalyst and involving an easy-to-prepare and isolable organoborate reagent. Reactions reach completion in just a few minutes at room temperature. This advance was leveraged in the enantioselective preparation of intermediates previously used to generate racemic PPAPs, along with the first enantioselective synthesis of nemorosonol (14 steps, 20% yield) and its one-step conversion to another PPAP, garcibracteatone (52% yield).
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Dr. Sepand Nistanaki | Jacobsen Group, Harvard University
Catalytic Asymmetric Synthesis of Quaternary Ammonium Ions
Chiral quaternary ammonium ions constitute an important class of compounds applied in various contexts, including as catalysts and as medicines. Despite this, the enantioselective synthesis of stereogenic-at-nitrogen ammonium ions has proven challenging, and the few known approaches suffer from various limitations, including moderate-to-poor enantioselectivity, limited substrate scope, and/or the requirement of stoichiometric chiral reagents. My talk will discuss the development of highly enantioselective, hydrogen-bond-donor catalyzed alkylations of arylamines to produce stereogenic-at-nitrogen ammonium ions.
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Dr. Tin Pham | Scheck Group, Tufts University
A Chemical Mechanistic Path Leads the Way to Cellular Argpyrimidine
Argpyrimidine (APY) is a methylglyoxal-derived advanced glycation end-product (AGE) that has been associated with multiple diseases. As APY forms without an enzyme, it remains exceptionally difficult to pinpoint where APY is likely to be found, both on individual proteins and in cells. In this study, we used a peptide model system and mass spectrometry analysis to investigate the chemical mechanism through which APY arises from methylglyoxal (MGO), a biologically relevant glycating agent. Consistent with other proposed APY formation mechanisms, our results identify AGE species with a mass change of [M+144], presumably including tetrahydropyrimidine (THP), as a direct precursor to APY. However, our results rule out previously proposed reductone or oxidative decarboxylation mechanisms. Instead, we show that a formal oxidation step is not required, and that formate is released instead of CO2. We further show the potential for a nearby residue such as Tyr to assist in the APY formation mechanism by acting as a general base. These experiments also reveal that phosphorylated Tyr or Ser residues can also promote equivalent levels of APY formation, despite introducing additional negative charges that we previously showed to impede glycation. Guided by these mechanistic insights and a newly defined role for phosphorylated residues on glycation substrates, we performed quantitative bottom-up proteomics analysis for MGO-treated cells. Gene ontology and functional annotation clustering analyses for APY-modified proteins suggested a correlation with phosphorylation-related terms (e.g. kinase activity or protein phosphorylation), which was validated using synthetic phosphopeptide substrates. Collectively, these data define a chemical mechanistic path to APY and suggest significant crosstalk between cellular phosphorylation and glycation events including APY formation.
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Robert-Cristian Raclea | Movassaghi Group, Massachusetts Institute of Technology
Total Synthesis of (+)-Hazuntiphylline, (–)-Anhydrohazuntiphyllidine, and (–)-Hazuntiphyllidine
The first total synthesis of the bisindole alkaloids (+)-hazuntiphylline, (–)-anhydrohazuntiphyllidine, and (–)-hazuntiphyllidine is described. We envisioned an efficient synthetic strategy based on a plausible biosynthetic hypothesis for the rapid assembly of these complex alkaloids via successive methylenation of an oxidized variant of the natural product (–)-mehranine. Our concise synthesis of these alkaloids required the development of completely stereoselective double alkylation sequences of transiently formed C3-enamines and precise timing for hydration of intricate intermediates. Whereas homodimerization of a C3-methylene mehranine-derivative exclusively gave (–)-3-epi-anhydrohazuntiphyllidine, an alternative alkylation cascade was developed to afford the natural products (–)-anhydrohazuntiphyllidine and (+)-hazuntiphylline. Insights gained in these studies concerning the intermediacy of hydrated intermediates enabled a completely stereoselective synthesis of (–)-hazuntiphyllidine, the most complex member of the Hazunta alkaloids. We discuss our hypothesis for the rapid assembly of these intriguing alkaloids, including our completely controlled access to both the natural and epimeric C3-quaternary stereochemistry of anhydrohazuntiphyllidine, and analysis of plausible biosynthetic intermediates including a sensitive methylenebisdesmethylmehranine derivative, highlighting divergent pathways to each natural alkaloid based on the order of C–C and C–N bond formation and the hydration of putative intermediates.
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Brandon Singh | Ting Group, Brandeis University
Insight into FtmOx1 through substrate analogs
Endoperoxides are a group of natural products that have been shown to have potent desirable bioactive properties. Despite multiple of these natural products being isolated, few endoperoxidases, enzymes that catalyze the formation of these compounds, have been reported. FtmOx1, which catalyzes the formation of verruculogen, is one such enzyme. Through the use of isotope and substrate analogs we have probed the mechanism of FtmOx1 to better understand how nature catalyzes this unusual and desirable reaction.
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Dr. Alicia Wagner | Manetsch Group, Northeastern University
Identification and structural optimization of 2-amido-pyrazines as novel P. falciparum inhibitors
The recent rise in drug resistance against current malaria treatment options necessitates the identification of alternative malaria targets and new antimalarial drugs. Plasmodium falciparum formate-nitrite transporter (PfFNT), a lactic acid efflux pump, has been identified as one such druggable target, though the current inhibitor class is not drug-like as substrates possess a PAINs moiety. Through a virtual high-throughput screen (vHTS), cheminformatics-driven down selection, and structure activity relationship (SAR) studies, we have identified a 1,2,4-triazole-containing carboxamide scaffold; while the most promising triazole displayed 519 nM potency against the asexual blood stages of the parasite, this activity was unable to be surpassed. Scaffold hopping efforts then revealed six alternative cores with up to a 31-fold increase in potency from the aforementioned frontrunner triazole. Further modifications to the molecule periphery have enabled the identification of numerous molecules with single-digit nanomolar potency and improvements towards metabolic stability and aqueous solubility. Lead compounds have proven to be orally bioavailable in pharmacokinetic studies and efficacious in an in vivo efficacy study. However, a functional assay that measures the pH of the parasite cytosol in real time suggests that hits are not targeting PfFNT. Upon pressuring the parasite with high levels of compound, resistance was successfully generated. Following whole genome sequencing of these mutants, several potential targets were identified and are currently being investigated further. Additional structure-activity and structure-property relationship studies are ongoing to further optimize this promising new chemotype.
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Aiden Wang | Johnson Group, Massachusetts Institute of Technology
Antibody-Bottlebrush Conjugated Degraders (ABCDs) – novel constructs for targeted protein degradation therapy
Proteolysis-Targeted Chimeras, or bifunctional protein degraders, are promising candidates for next-generation cancer therapy. Their unique mechanism of action targets the degradation of traditionally undruggable cancer-related proteins, leading to outstanding efficacy in-vitro. However, their road to clinical approval have been hampered by issues of poor pharmacokinetics and off-target toxicity. Through tandem innovations in polymer and drug–linker chemistry, we present Antibody–Bottlebrush Conjugated Degrader (ABCD) constructs that enable targeted delivery of Cereblon (CRBN)-based PROTACs. ABCDs consist of an antibody designed to target antigens expressed preferentially on cancer cells tethered to a biocompatible bottlebrush polymer prodrug (BPD) with polyethylene glycol sidechains. Through novel chemical strategies, clinically relevant, Cereblon (CRBN)-based protein degraders can be covalently conjugated onto the BPD in ratios up to two orders of magnitude greater than traditional antibody–drug conjugates, featuring tunable drug release kinetics that translate into measurable differences in protein degradation efficacy. We show that ABCDs deliver protein degraders with high efficacy through a mechanism involving target engagement, cell uptake, and release of PROTAC payload. ABCDs demonstrate excellent in-vivo safety profiles, as well as improved target accumulation and efficacy in antigen-expressing murine tumor models. This work provides a novel solution to the overcome the challenges in clinical translation of PROTACs using a safe, scalable and well-defined targeted delivery platform.
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