8:00 am Registration and Breakfast
9:00 Organizer's Welcome
Alexander Radosevich, Associate Professor of Chemistry Massachusetts Institute of Technology.
Alexander Radosevich is originally from Waukegan, IL. He received his B.S. degree from the University of Notre Dame (2002) and his Ph.D. degree from the University of California at Berkeley (2007). After completing an NIH postdoctoral fellowship at MIT with Prof. Daniel G. Nocera, he joined the faculty at the Pennyslvania State University in 2010. In August of 2016, he returned to the Department of Chemistry at MIT as an Associate Professor. He works at the interface of inorganic and organic chemistry to design new chemical reactions. In particular, his interests concern the invention of compositionally new classes of molecular catalysts based on inexpensive and earth-abundant elements of the p-block. This research explores the connection between molecular structure and reactivity in an effort to discover new efficient and sustainable approaches to chemical synthesis. He has been the recipient of a number of awards including an Amgen Young Investigator’s Award (2015), a Sloan Research Fellowship (2014), and an NSF CAREER Award (2014).
9:10 Morning Chair's Remarks
Haibo Liu, Senior Scientist, Celgene
9:15 Xenoprotein engineering via synthetic libraries
Zak Gates, Brad Pentelute Group, MIT.
Chemical methods have enabled the total synthesis of protein molecules of ever increasing size and complexity. Yet, methods to engineer synthetic proteins comprising non-canonical amino acids have not kept pace, even though this capability would be a distinct advantage of the total synthesis approach to protein science. Toward bridging this gap, an approach to protein engineering based on the screening of synthetic one-bead one-compound protein libraries will be presented. Particular emphasis is placed on the development of FACS-based analysis of on-bead screens for binders, with the goal of approaching the screening throughput of cell surface display approaches.
9:35 Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)
Rocco Policarpo, Matthew Shair Group, Harvard University.
NNMT is a metabolic enzyme responsible for the methylation of nicotinamide (NCA). NNMT overexpression has been linked to diabetes, obesity, and a variety of cancers. Successful development of potent and selective NNMT inhibitors would help us better understand NNMT’s role in various diseases, potentially enabling new treatments for metabolic disease and some cancers. To this end, we utilized structure-based (computationally-guided) rational design to develop potent inhibitors of NNMT. We noted that in the NNMT cocrystal structure the NCA and SAM nitrogen and sulfur atoms, respectively, are positioned ca. 4 Å apart and reside in a tunnel that facilitates an SN2-type methyl transfer reaction. We envisioned an alkyne as the optimal linker between an NCA-like and a SAM-like fragment. The resultant alkynyl bisubstrate inhibitor, NS1, was synthesized asymmetrically in thirteen steps and found to be a 6 nM NNMT inhibitor, the most potent reported to date.
9:55 Chemo-enzymatic Site-specific Reversible Modifications of Protein
Kevin Moulton, Sunny Zhao Group, Northeastern University.
Spatial and temporal control are hallmarks of complex chemical systems. As such, methods to control the ‘on’ and ‘off’ states of molecules via reversible modifications are highly desirable. A special case of reversible modification is referred to as caging, a process in which a molecule is covalently modified to form a chemical derivative that typically reduces one or more functions of the molecule. This chemical derivative can be cleaved by orthogonal stimuli (e.g., light, chemical reagents, etc.) to regenerate the original native molecule and thus recover the function. Many previous approaches toward protein photocaging are non-specific and primarily target nucleophilic residues. Glutamine, while traditionally considered chemically inert, represents an intriguing and relatively unexplored alternative target for caging. Our lab has recently developed a novel method for site-specific reversible modification of proteins using transglutaminase (TGase, EC 184.108.40.206) to incorporate amine-containing photolabile groups onto substrate glutamine residues via a transamidation reaction. Several amine-containing photocaging groups – including derivatives of the robust nitrobenzyl and less-explored nitrophenylethyl chromophores – were found to be TGase substrates, thus expanding the repertoire of installation and functional groups available. We have shown that cleavage of the UmuD protein is abolished by TGase-mediated photocaging of Q23 and Q36 and subsequently restored upon UV photolysis. Moreover, we are also exploring additional modifications that can be reversed by other stimuli. These newly-developed reversible modifications of proteins should have broad applications in chemistry, biology, medicine, and material science.
10:15 Investigations into Catalytic Cadogan Cyclization: N-N and C-N Bond Forming Heterocyclizations via PIII/PV=O Redox Cycling
Trevor Nykaza, Alex Radosevich Group, MIT.
In addition to their well-known Lewis basic reactivity, trivalent phosphorus compounds are valuable stoichiometric reagents for a range of reductive O-atom transfer reactions involving the conversion of R3PIII to R3PV=O. Despite great utility, the inefficient generation of stoichiometric phosphine oxide waste inherent to these methods is regarded as a key limitation. It is demonstrated that a substoichiometric amount of phosphine oxide can be reduced in situ to catalyze the exhaustive deoxygenation and cyclization of o-functionalized nitrobenzene derivatives via PIII/PV=O cycling – providing access to useful heterocyclic skeletons.
10:35 Coffee Break with Poster Viewing with Even numbered Presenters
11:15 KEYNOTE PRESENTATION:
Emily Balskus, Morris Kahn Associate Professor of Chemistry and Chemical Biology, Harvard University.
The human body is colonized by trillions of microorganisms that exert a profound influence on human biology, in part by providing functional capabilities that extend beyond those of host cells. In particular, there is growing evidence linking chemical processes carried out by the microbial inhabitants of the gastrointestinal tract to both health and disease. However, we still do not understand
the vast majority of the molecular mechanisms underlying this phenomenon. A major reason for this knowledge gap is the difficulty linking functions associated with the human gut microbiota to specific microbial enzymes. This talk will discuss my lab’s efforts to discover, characterize, and manipulate new gut microbial enzymes and metabolic pathways, including transformations that produce disease-associated microbial metabolites. Gaining a molecular understanding of gut microbial enzymes will not only enhance our ability to identify the genes encoding metabolic activities in microbiome sequencing data, but will also help to elucidate the mechanisms by which these organisms affect human biology. Ultimately, this work should enable efforts to treat and prevent disease by manipulating gut microbial metabolism.
12:15 pm Networking Lunch with Poster Viewing
1:30 Afternoon Chair's Remarks
Masayuki Wasa, Associate Professor, Boston College.
1:35 Targeting the Prolyl Isomerase Pin1 with Covalent Inhibitors
Benika Pinch, Nathanael Gray Group, Harvard University.
Pin1 regulates the function and stability of specific phosphoproteins by catalyzing the cis/trans isomerization of peptidyl-prolyl bonds that follow phosphorylated serine or threonine residues. In breast and pancreatic cancer, Pin1 promotes transformation by stabilizing oncogenes and inactivating tumor suppressors. Using structure-based design, we developed and characterized peptidomimetic inhibitors that form a covalent adduct with a critical cysteine residue, Cys113, in the Pin1 active site. Through iterative rounds of structure activity relationship (SAR) studies, the lead compounds were optimized to generate the first highly potent, cell permeable, and Pin1-selective covalent inhibitors. These compounds can be used as cellular probes to study Pin1 biology, and to assess the effectiveness of Pin1 inhibitors as therapeutic agents in oncogenesis. In parallel to inhibitor development, we assessed the expected phenotype of Pin1 loss by employing a chemical genetic strategy to achieve targeted Pin1 degradation in TNBC MDA-MB-231 and 8988T cells.
1:55 In vitro selection of glycopeptides that target HIV broadly neutralizing antibodies
Jennifer Bailey, Isaac Kraus Group, Brandeis University.
Design of immunogens for HIV vaccine development has been a challenge due to numerous mechanisms of viral immune escape that result in elicitation of non-neutralizing or strain-specific antibodies. However, ~20 % of HIV-infected individuals eventually produce broadly neutralizing antibodies (bnAbs). Many bnAbs, such as 2G12 and members of the PGT family, bind to high-mannose carbohydrates on HIV envelope glycoprotein gp120. Inoculation with glycan-rich structures that mimic bnAb epitopes may elicit a “bnAb-like” immune response that protects against HIV infection. In order to design such structures, our lab has developed methods for in vitro selection of glycosylated libraries. In one method, we use alkyne-azide “click” chemistry to attach high-mannose carbohydrates to mRNA-display libraries, generating multivalent glycopeptides with up to ten trillion sequences. Our selection method has previously yielded glycopeptides that bound to bnAb 2G12 with low to sub-nanomolar KDs. In this presentation, we will discuss modifications to our system, including cyclization of peptides, and the application to new targets in the PGT antibody family.
2:15 The Utilization of Sulfonylhydrazones as New Radical Precursors for Asymmetric Radical Reactions via Co(II)-Based Metalloradical Catalysis
Yong Wang, Peter Zhang Group, Boston College.
Among recent advances in devising different strategies for stereoselective homolytic reactions, metalloradical catalysis (MRC) has emerged as a conceptually new approach for controlling stereoselectivity of radical reactions. As stable metalloradicals, cobalt(II) complexes of D2-symmetric chiral amidoporphyrins [Co(D2-Por*)] have proven to be effective catalysts for asymmetric radical transformations through catalytic generation of metal-stabilized organic radicals, such as α-metalloalkyl radicals, as the key intermediates. Recently, we have expanded the applications of Co(II)-based MRC by utilizing in situ-generated diazo compounds, such as aryl diazomethanes and alkyl diazomethanes, as new radical precursors. With aldehyde-derived sulfonyl hydrazones as the diazo surrogates, we have demonstrated their utilities for various asymmetric transformations, including intermolecular radical cyclopropanation of alkenes and intramolecular radical alkylation of C–H bonds. Through the development of new chiral ligands, these homolytic processes have enabled the delivery of various cyclic compounds in high yields with excellent control of stereoselectivity.
2:35 Photoredox Generated Carbonyl Ylides Enable the Total Synthesis of Classical Lignan Natural Products
Edwin Alfonzo, Aaron Beeler Group, Boston University
Photochemical generation of carbonyl ylides from epoxides was first reported, independently, by Griffin, Lee, and Huisgen in the early 1970’s. Following these disclosures, numerous mechanistic studies detailing the factors that govern formation and 1,3-dipolar cycloaddition of carbonyl ylides have been divulged. Yet, despite these efforts, the practical use of these intermediates as a common synthetic tool for target oriented synthesis has yet to be demonstrated. In this talk, I will showcase the rational design of new photoredox catalysts that have greatly expanded the scope of carbonyl ylide formation which are used in cycloadditions to generate dihydro and tetrahydrofurans. Additionally, the application of this reaction to the total synthesis of all six members of the classical lignan family of natural products will be delineated, providing the first unified approach to these molecules that have shown promising biological actions.
2:55 Refreshment Break with Poster Viewing with Odd Numbered Presenters
3:30 Targeting Diabetic HLA-DQ8 with a Peptidomimetic Fragment-based Approach
Daniel Sheehy, Arturo Vegas Group, Boston University
Type 1 diabetes is a global epidemic affecting over 30 million people, and is one of the most common endocrine and metabolic conditions occurring in childhood. The disease is characterized by the autoimmune destruction of insulin secreting β-cells leading to loss of blood glucose regulation. Despite advances in exogenous insulin therapies, these individuals still suffer complications including heart failure, retinopathy, neuropathy, and ketoacidosis. Currently, there are no interventional therapies to treat the underlying autoimmunity. Genetic susceptibility to type 1 diabetes has been strongly linked to the major histocompatibility complex protein HLA-DQ8 and its presentation of pancreatic autoantigens. Here, we showcase our efforts towards developing novel synthetic ligands to the diabetic HLA-DQ8 protein using a peptidomimetic fragment-based approach to inhibit the diabetic HLA-DQ8 autoantigen presentation. Through the development of these ligands, we explore a potential therapeutic approach for delaying or preventing type 1 diabetes and other related autoimmune diseases.
3:50 Substrate-Selective Inhibitors that Reprogram the Activity of the Human Metalloprotease Insulin-Degrading Enzyme to Spare Insulin but Allow Glucagon Cleavage
Juan Pablo Maianti, David Liu Group, Harvard University
Enzymes that act on multiple substrates are common in biology but pose unique challenges as therapeutic targets. Insulin-degrading enzyme (IDE) is a zinc metalloprotease that modulates blood glucose levels by cleaving insulin, a peptide hormone that lowers blood glucose levels (Nature 2014, 511, 94-8). However, IDE also degrades glucagon, a peptide hormone that elevates blood glucose levels and thus opposes the effect of insulin. IDE inhibitors to treat diabetes therefore must block insulin degradation, but not glucagon degradation, in contrast to what is achievable through the traditional mode of action of the vast majority of known enzyme inhibitors, which block activity on all substrates. We developed a high-throughput screen for non-active-site IDE ligands and discovered potent (EC50’s < 1 nM) and highly specific small-molecule inhibitors that bind away from the active site and alter IDE’s substrate selectivity by reshaping its substrate-binding pocket, unlike traditional protease inhibitors that disrupt the enzyme’s catalytic mechanism. Remarkably, these substrate-selective IDE inhibitors potently and completely abolish insulin degradation without shutting down IDE cleavage of glucagon, even at saturating inhibitor concentrations. X‑ray co-crystal structures of an IDE-ligand and an IDE-ligand-glucagon “ternary complex” elucidated the molecular basis of substrate-selective inhibition, revealing how the ligand allows glucagon binding and cleavage, while inducing steric clashes that exclude insulin from the substrate-binding cavity of the IDE-inhibitor complex. These findings suggest a path forward for the development of IDE-targeting therapeutics, and also offer a blueprint for modulating other enzymes in a substrate-selective manner to unlock their therapeutic potential.
4:10 KEYNOTE PRESENTATION: Discovery of AMG986, a potent, selective and orally bioavailable APJ agonist for the treatment of heart disease
Paul Dransfield, Principal Scientist, Department of Medicinal Chemistry, Amgen Discovery Research
The G protein-coupled receptor, APJ (APLNR), and its endogenous peptidic ligand (apelin) have been implicated in mediating multiple beneficial effects on cardiovascular function. Efforts to employ apelin peptides therapeutically have been hindered by their very short half-lives. This presentation will describe the small molecule drug discovery process from optimizing a small molecule high-throughput screening hit through to the identification of the APJ agonist AMG 986. A phase 1 clinical trial is currently underway evaluating AMG 986 in healthy volunteers and heart failure patients
5:10 Closing Remarks
Angel Guzman-Perez, Director of Medicinal Chemistry, Amgen Discovery Research
Angel Guzman-Perez is a Director of Medicinal Chemistry at Amgen, where he leads a group of scientists charged with the delivery of leads and clinical candidates in the areas of oncology, inflammation, neuroscience, and cardiovascular disease. Prior to joining Amgen, Angel began his professional career at Pfizer working in the areas of cardiovascular, obesity, osteoporosis, frailty and diabetes research. In over two decades in the pharmaceutical industry, he has contributed to the discovery of multiple leads and clinical candidates in in a broad range of target classes. Angel has an interest in the application of in silico models in drug design and has recently been involved in the application of AI and deep learning approaches to drug discovery at Amgen. Angel attained a Bachelor’s degree in chemistry at the National Autonomous University of Mexico, and his Ph.D. from Harvard University. At Harvard, he worked under the direction of Nobel laureate E. J. Corey on the asymmetric synthesis of natural products with quaternary stereocenters.
5:20 Networking Reception with Poster Viewing
6:30 Close of BSOBC 2018