Speakers
Keynote Speakers
Alison Wendlandt, Associate Professor of Chemistry, MIT
Alison Wendlandt is an Associate Professor of Chemistry at the Massachusetts institute of Technology. Alison is originally from Colorado, and received her B.S. from the University of Chicago and her Ph.D. from the University of Wisconsin - Madison under the guidance of Shannon Stahl. Alison was a postdoctoral fellow at Harvard University in the Jacobsen research group, until beginning her independent career at MIT in 2018. The Wendlandt group is interested in the development and mechanistic elucidation of new selective catalytic reactions.
Matthew J. LaMarche, Head of Integrated Drug Discovery and Head of Medicinal Chemistry, US, Sanofi
Matt is a leader in small molecule drug discovery with over 20 years of experience across biopharmaceutical and biotechnology companies. Matt is the Site Head for Integrated Drug Discovery and Head of Medicinal Chemistry for Sanofi in Cambridge, MA. Previously, he held roles of Associate Director, Group Head at Novartis, and Principal Scientist at Millennium Pharmaceuticals. Matt’s drug discovery career spans various therapeutic modalities and diverse disease areas such as metabolism, infectious diseases, neurology, and oncology. Matt and his teams have discovered numerous new chemical entities (NCEs) which have achieved clinical milestones such as batoprotafib and darovasertib. Matt has over 70 publications and patents, serves on the American Chemical Society Pharma Leaders committee, the AACR Chemistry in Cancer working group, an NIH study section on contraception research, and was the chair of the 2019 Gordon Research Conference on Natural Products and Bioactive Compounds. Matt received his Ph.D. in organic chemistry/natural product total synthesis from the University of Pennsylvania, and B.S. in biochemistry from the University of Notre Dame.
Student/Postdoc Speakers
Imani McDonald , Kritzer Lab at Tufts University
Development of GABARAP-specific stapled and N-methylated peptide modulators of autophagy
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Autophagy is an essential recycling pathway where cytosolic material is shuttled to the lysosome for degradation. In advanced-stage cancers, autophagy can aid tumor progression and can promote resistance to DNA-damaging chemotherapy. Nonspecific autophagy inhibitors like chloroquine can resensitize chemoresistant cancer cells, but there are few highly selective small-molecule autophagy inhibitors. Protein-protein interactions involving autophagy proteins LC3 and GABARAP are promising targets for autophagy inhibition. Using structure-based design, we developed minimized stapled peptides and N-methylated peptides with sub-micromolar affinity for GABARAP. These peptides are promising as potential combination therapies with DNA-damaging agents. They also can be used as building blocks for autophagy-mediated targeted protein degraders.
Meihui Yi, Xu Lab at Brandeis University
In-situ supramolecular nanotubes for extrinsic lytic cancer cell death
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Two distinct immunoresistance mechanisms, plasma membrane repair (PMR) and adenosine receptor signaling, in the hostile tumor microenvironment (TME) remain unmet challenge in cancer therapy. Here, we show that alkaline phosphatase (ALP), an ectoenzyme overexpressed in TME to produce adenosine, catalyzes in-situ supramolecular nanotubes (iSNT) to mediate lytic cancer cell death. ALP on immunosuppressive cancer cells transforms precursors into iSNT. This process triggers endocytosis and ectocytosis, disrupting focal adhesion, depolymerizing cytoskeletons, inducing mitochondria fission, and causing swelling of endoplasmic reticulum, ultimately leading to cataclysmic membrane rupture and subsequent lytic cell death. By overwhelming PMR and targeting multiple immunoresistance mechanisms, ALP-catalyzed iSNT reduces drug resistance. This study highlights an approach to target cancer cells by utilizing, but not inhibiting, their survival mechanisms, potentially opening doors to treatments for other diseases.
Zhenyu Zhu, Zhang Lab at Boston College
Enantioselective Radical Process for Amination of Enamines: Asymmetric Synthesis of Chiral a,β-Diamino Acid Derivatives
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A new catalytic radical process has been developed for asymmetric amination of enamines with organic azides via Co(II)-based metalloradical catalysis (MRC). The Co(II)- catalyzed aza-allyl amination involves the generation of azaallyl radicals as the key intermediates from hydrogen atom abstraction from N–H bonds by initially formed a-Co(III)-aminyl radicals. Through the employment of well-designed D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-based metalloradical system can
activate different fluoroaryl azides for azaallyl amination of various enamines under mild conditions, enabling the stereoselective synthesis of a,β-diamino acid derivatives in good to high yields with high enantioselectivities. Combined computational and experimental studies further support the underlying stepwise radical mechanism for the new Co(II)-catalyzed amination process. The resulting enantioenriched a,β-diamino acid derivatives that contain chiral a-tertiary amine centers and imine functionalities may serve as useful intermediates for stereoselective organic synthesis.
Sam Whedon, Cole Lab at Harvard Medical School
Chemoenzymatic methods for characterizing epigenetic enzyme activity
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Reversible modification of the histone H3 N-terminal tail is critical in regulating chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. We have developed an engineered sortase transpeptidase that simplifies preparation of modified nucleosomes, a chromatin model, for characterization of epigenetic enzyme activity. This sortase also effectively cuts and tags histone H3 tails from endogenous histones, enabling quantitative middle down proteomics with tandem mass tags. In this way we measure changing patterns of histone post-translational modifications following treatment with histone deacetylase inhibitors, illustrating the potential utility in characterizing specific effects of epigenetic therapeutics.
Bjarne Jonas Silkenath, Raines Lab at MIT
Synthesis of Carbohydrate Mimics: As glmS Riboswitch Activators and Potential Antibiotics
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A new target to fight multi-resistant bacterial strains is the glmS-riboswitch. In general, riboswitches regulate gene expression in dependence of a metabolite. Among all the different classes of riboswitches, the glmS-riboswitch assumes a unique role, as it does not simply regulate gene expression in response to increasing metabolite concentrations, but it does so by an enzymatic activity. This RNA segment is encoding for the GlmS-enzyme that is essential for the formation of glucosamine-6-phosphate (GlcN6P), an important building block in the early steps of the bacterial cell wall biosynthesis. At elevated concentrations, GlcN6P can bind to the glmS-riboswitch and induce a self-cleavage reaction, resulting in the degradation of the downstream mRNA.
Compounds that can bind to the glmS-riboswitch and induce the self-cleavage reaction, but cannot be metabolized by the bacterium, are an ideal substance class for new antibiotics.
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Here I report the synthesis of GlcN6P mimics were the ring oxygen is replaced by sulfur giving Thia-GlcN6P a potent activator of the glmS riboswitch. Furthermore, carbasugars, molecules where the ring oxygen is replaced by carbon are reported. In these carbasugars the newly introduced 5a carbon offers room for derivatization. A large library of novel 5a modified carba GlcN derivatives have been synthesized.
Valerie Wright, Torok Lab at UMass Boston
Catalyst- and Solvent-free Green Synthesis of Heterocyclic Building Blocks, Drug Candidates, APIs by High Hydrostatic Pressure
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The development of non-traditional activation methods, such as microwaves, ultrasounds, mechanochemistry or high hydrostatic pressure (HHP) is considered as one the most important contributors to the development of green synthetic processes. Among these methods, HHP is well-suited for industrial production; the large-scale instrumentation is broadly available, at this time focusing on food processing applications. While high-pressure organic synthesis, is still in its infancy extensive developments expected in the near future. HHP applies mechanical compression force to initiate transformations, let those be the inactivation of pathogens and enzymes, or the activation of chemical reactions. The pressure range of these reactions (2-20 kbar) significantly exceeds that of the typical chemistry. Here, we will describe our recent efforts on HHP-initiated organic reactions, with emphasis on catalyst- and solvent-free synthesis of heterocycles, derivatized sulfonamides, synthetic antioxidants, and a few drugs to illustrate the potential broad applicability of this technique.
Bin Liu, Johnson Lab at MIT
Antibody bottlebrush prodrug conjugates (ABCs) as a new platform for targeted cancer therapy
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Antibody drug conjugates (ADCs), which feature a monoclonal antibody (mAb) for cell targeting linked to a cytotoxic payload for cell killing, are a remarkably effective class of targeted therapeutics. Despite their success, however, ADCs have fundamental chemical limitations that limit their payload diversity, precluding the use of most potential payloads and payload mechanisms of action (MoA). Moreover, the emerging perspective that ADCs operate in part via passive targeting mechanisms suggests opportunities to engineer next-generation ADCs based on optimized prodrug scaffolds. In this talk, I will introduce a fundamentally new antibody-targeted prodrug platform which we refer to as “Antibody Bottlebrush prodrug Conjugates (ABCs)” to overcome these challenges. ABCs feature an IgG1 mAb covalently conjugated to the terminus of a compact bivalent bottlebrush prodrug (BPD). The latter contains payloads bound via cleavable linkers and hydrophilic poly(ethylene glycol) (PEG) branches on each repeat unit, allowing the use of a wide range of payloads and linkers with drug-to-antibody ratios (DARs) two orders-of-magnitude greater than traditional ADCs without negatively impacting the physical properties of the mAb. The unprecedented modularity of ABCs is highlighted by the synthesis of >10 different variants for distinct targets and incorporating traditional as well as novel payload MoAs (e.g., protein degraders) with potencies spanning several orders-of-magnitude and combined “theranostic” payloads. ABCs display excellent target engagement, cell uptake, and efficacy compared to commercial ADCs Kadcyla and Enhertu in tumor-bearing mouse models with no discernable toxicities, suggesting that they hold immense promise for clinical translation.
Paul Onnuch, Liu Lab at Harvard University
Aminative Suzuki–Miyaura Coupling
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We report the incorporation of a formal nitrene insertion process into the Pd-catalyzed Suzuki–Miyaura cross-coupling, altering the products from C–C-linked biaryls to C–N–C-linked diaryl amines. This discovery effectively joins the Suzuki–Miyaura and Buchwald–Hartwig coupling pathways to the same starting-material classes, and the protocol allows for the repurposing of advanced drug-like intermediates. A combination of a bulky ancillary ligand, unconventional bases, and commercially available amination reagent enables this transformation, resulting in a highly general and reliable process. The reaction is efficient across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility in the order of bond-forming events, suggesting potential for the aminative cross-coupling concept to be expanded to encompass diverse nucleophiles and electrophiles, as well as four-component variants.
Kaitlyn Corazzata, Schaus Lab at Boston University
Synthesis of Modified Nucleotides for saRNA Applications: Electrochemical Installation of Fluorinated Motifs on Purines and Pyrimidines​
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RNA therapeutics have revolutionized modern medicine as seen with mRNA COVID-19 vaccines. However, challenges associated with mRNA include adverse immune effects and large and frequent doses. saRNA (self-amplifying RNA) poses as a potential alternative. Clinical success has been limited as wild type saRNA evokes a strong interferon response and commonly used modified nucleotides in mRNA such as N1-methylpseduouridine have demonstrated minimal protein expression in saRNA constructs. However, a preliminary screen identified several modified nucleotides that both increase protein expression and suppress interferon response. To expand the potential library of modified nucleotides, we are synthesizing a series of fluorinated nucleotides, as fluorine is known to induce unique pharmacological properties. We successfully incorporated a fluorinated nucleotide in saRNA and observed mCherry reporter protein expression. Of various synthetic techniques, we are particularly interested in electrochemical methodologies to install fluorinated groups on the 5’ position of uracil, the synthetic precursor to modified uridine and cytidine triphosphates. Under constant current in a single cell with the IKA Electrasyn 2.0, we investigated difluoromethylation and trifluoromethylation reactions, using sodium difluoromethanesulfinate and sodium trifluoromethanesulfinate respectively. Method development has afforded substrate scope expansion to various purines and pyrimidines in yields of up to 80%, many of which have no literature precedent for these electrochemical transformations. Efforts are ongoing, and future direction is aimed at further expanding the substrate scope for the electrochemical di- and trifluoromethylation of purines and pyrimidines as well as expanding the fluorinated nucleotide library for testing in saRNA.