Bradley L. Pentelute
PROFESSOR OF CHEMISTRY AT MIT
Bradley L. Pentelute, Professor of Chemistry. He is also an Associate Member, Broad Institute of Harvard and MIT, an Extramural Member of the MIT Koch Cancer Institute, and Member, Center for Environmental Health Sciences MIT. He received his undergraduate degree in Psychology and Chemistry from the University of Southern California, and his M.S and Ph.D. in Organic Chemistry from the University of Chicago with Prof. Steve Kent. He was a postdoctoral fellow in the laboratory of Dr. R. John Collier at Harvard Medical School, Microbiology.
Andrew T. Parsons
DIRECTOR IN PROCESS DEVELOPMENT AT AMGEN
Andrew Parsons is a Director of Process Development in the Pivotal and Commercial Synthetics group at Amgen, Inc. Andrew received his A.B. in Chemistry from Bowdoin College (2005), conducting undergraduate research with Professor Richard D. Broene. He obtained a Ph.D. from the University of North Carolina at Chapel Hill (2010) with Professor Jeffrey S. Johnson for research on catalytic annulations of strained cycloalkanes. After completing his PhD, he joined Professor Stephen L. Buchwald’s group at MIT as an NIH postdoctoral fellow where he developed new catalytic trifluoromethylation reactions. He then started his career in process chemistry by spending a year in the Chemical Development group at Bristol-Myers Squibb in New Brunswick, NJ. In 2013 Andrew joined Amgen’s Process Development group in Cambridge, MA, where he has since supported the development efforts for numerous clinical and commercial assets. Most recently, Andrew led the process chemistry team that developed and commercialized the drug substance manufacturing process for LUMAKRAS (sotorasib).
Mingkai Zhang (he/him)
BOSTON COLLEGE - MORKEN GROUP
Escaping from Symmetry: Two-step Synthesis of Enantioenriched Disubstituted Nortricyclanes — Bioisosteres of meta Substituted Arenes
In recent years, more and more effort has been put into the development of arene bioisosteres, the replacement of flat aromatic rings with saturated, rigid polycycles. This replacement may improve pharmacokinetic properties while retaining bioactivity, and this concept is known as escaping from flatland. Though many scaffolds perform well as bioisosteres of para substituted arenes, meta substituted benzene bioisosteres are less studied. There are only a few rigid bicyclic motifs that have been investigated, and they are either achiral or prepared as racemates. Considering arene bioisosteres are meant to mimic arenes in pharmaceuticals whose role is to bind to chiral proteins, sugars, RNAs etc., to achieve pharmacological functions, enantioenriched bioisosteres may be more effective. Herein, we introduce the concept of “escaping from symmetry” and report a concise, asymmetric synthetic route to meta benzene bioisosteres by Suzuki cross-coupling. This reaction can quickly build up an array of boronic ester substituted arene bioisosteres in high yield and enantioselectivity and the boronic ester can be functionalized with multiple functional groups. Detailed mechanism and bioactivity studies are undergoing.
Olivea M. Vasquez (she/her)
TUFTS UNIVERSITY - BENNETT GROUP
Versatile Synthetic Route to 2,4-diamino-2,4,6-trideoxyhexoses (DATDH): Bacterial, Rare, and Unusual Deoxy-amino Sugars
A versatile synthetic route to various stereoisomers of 2,4-diamino-2,4,6-trideoxysugars in 6-7 steps and 21-33% overall yield is described. A key step in this pathway is the carbonyl reductive coupling of D- and L-threoninol or D- and L-allothreoninol to a phthalimido-allene pronucleophile mediated by a chiral Iridium-H8-BINAP catalyst allowing for installation of two new chiral centers in one, highly diastereoselective (>20:1 d.r.) step. The approach represents, to our knowledge, the first example using chiral α-amino, β-hydroxy alcohols as coupling partners in this Krische-type allylation chemistry. Furthermore, this approach provides a more concise, diastereoselective, and versatile method to access these deoxy-amino sugars than is currently available.
Caroline Millard (she/her)
NORTHEASTERN UNIVERSITY - NEGLECTED DISEASE DRUG DISCOVERY LAB
Medicinal chemistry optimization of the pyrazolopyridazine scaffold against Trypanosoma cruzi GSK-3β
Chagas disease, also known as American trypanosomiasis, is caused by the parasite Trypanosoma cruzi. The illness is life-threatening, mainly affects Latin American countries and approximately 7 million people are estimated to be infected worldwide. There are currently only two drugs that are used to treat Chagas Disease, nifurtimox and benznidazole, however, these are associated with toxicity and a lack of efficacy. Given the geographical distribution of patient populations, drug “repurposing” is utilized as a mechanism to reduce the time and cost of developing a drug. In this respect kinase inhibitors are attractive candidates and significant cross-reactivity between related kinetoplastids, which have highly similar kinomes, has been identified.
Our lab originally identified AZD5438 as a potent inhibitor of T. brucei, L. infantum and T. cruzi. Exploiting the similar kinomes across these pathogens, we are utilizing both structure driven, and ligand based medicinal chemistry optimization of the pyrazolopyridazine scaffold against T. cruzi. The main goals for further optimization are to (1) increase aqueous solubility and, (2) improve selectivity over human kinases while maintaining potency. These goals are not isolated from each other and are being considered simultaneously and a multiparameter optimization approach is being implemented to develop a lead compound within this series.
Marissa N. Lavagnino (she/her)
MASSACHUSETTS INSTITUTE OF TECHNOLOGY - RADOSEVICH GROUP
A Transient Dearomatization Strategy for the Tandem C/N-Difunctionalization of Nitroarenes
A catalytic method for the reductive transformation of nitroarenes into ortho-aminated and -annulated products will be discussed. The method operates via the exhaustive deoxygenation of nitroarenes by an organophosphorus catalyst and a mild terminal reductant to access aryl nitrenes, which upon ring expansion are trapped by amine nucleophiles to yield dearomatized 2-amino-3H-azepines. Treatment of these ring-expanded intermediates with acyl electrophiles triggers 6π electrocyclization to extrude the nitrogen atom and restore aromaticity of the phenyl ring, delivering a wide scope of 2-aminoanilide and benzimidazole products—important scaffolds in industrially relevant and bioactive molecules.
Jaron Mercer (he/him)
BROAD INSTITUTE OF HARVARD AND MIT - LIU GROUP
Continuous evolution of compact protein degradation tags regulated by selective cereblon molecular glues
Small molecule-triggered protein degradation tags (degrons) are powerful tools to study protein function and inform therapeutics development. Commonly used degrons, however, are large protein domains (typically >100 amino acids) that cannot be easily or cleanly installed in endogenous protein-coding genes in most cell types. We developed a phage-assisted continuous evolution platform for molecular glues (MG-PACE) and applied it to evolve zinc finger (ZF) degrons that engage cereblon (CRBN) only in the presence of orthogonal thalidomide derivatives. MG-PACE evolved a 36-amino acid ZF degron (SD40) that binds CRBN with high affinity in the presence of PT-179, a thalidomide derivative with no detected neosubstrate activity. The evolved degron is small enough to be efficiently inserted into targeted genomic sites in human cells using prime editing. Human proteins tagged with the evolved degron are rapidly and potently degraded by the otherwise-inert PT-179. High-resolution cryo-electron microscopy structures of SD40 in complex with CRBN-DDB1 bound to PT-179 or pomalidomide provide mechanistic insights into the evolution and molecular basis of SD40’s activity and specificity. Collectively, our efforts establish a system for the rapid evolution of molecular glue complexes with new specificities and compact ZF tags that overcome shortcomings associated with existing degrons.
Michael J. Strauss (he/him)
MASSACHUSETTS INSTITUTE OF TECHNOLOGY - BUCHWALD GROUP
Cu-Catalyzed C–N Bond-Forming Reactions Utilizing N1,N2-Diarylbenzene-1,2-Diamine Ligands
Ullman-type C –N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and lower cost of Cu. While the design of anionic ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. I will discuss the development of a new family of anionic ligands based on an N1,N2-diarylbenzene-1,2-diamine scaffold. Initially guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition, and (2) stabilize the active anionic CuI catalyst via non-covalent interactions. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine nucleophiles, including pharmaceutically relevant scaffolds, were efficiently coupled at room temperature. Combined experimental and computational studies support a mechanism of C–N bond formation that follows a catalytic cycle akin to the well-explored Pd-catalyzed variants. I will highlight how modification of the ligand scaffold to include a naphthyl residue drastically lowered the energy barrier to oxidative addition and provided a 30-fold rate increase relative to what is seen with other ligands. Collectively, these results establish a new class of anionic ligands for Cu-catalyzed C–heteroatom bond-forming reactions.
Zihao Wang (he/him)
BOSTON UNIVERSITY - PORCO GROUP
Assessment of Rocaglates and Targeted Derivatives in Glioblastoma
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and generally has a poor prognosis. Irrespective of treatment, which includes surgical resection, radiotherapy, and chemotherapy, almost all patients experience tumor recurrence, leading to mortality and a median survival of under 15 months. A large body of evidence suggests that the initiation, progression, metastasis, and recurrence of GBM are driven by a small subpopulation of cells within the tumor known as tumor-initiating cells (TICs). GBM-TICs play a pivotal role orchestrating drug resistance mechanisms, invasion, immune escape, and tumor relapse. As a prospective avenue for GBM intervention, targeted suppression of GBM-TICs holds promise. Recently, we identified novel rocaglate derivatives that can inhibit GBM-TICs with nanomolar (nM) EC50’s. Through comparative dose-response assays, we have found that the rocaglate derivatives exert a potent, dose-dependent cytotoxic effect on GBM-TICs. Efforts at target identification and functional assays will also be presented.
Claire Harmange Magnani (she/her)
BROAD INSTITUTE - SCHREIBER GROUP
Discovery of molecular glues using a synthetic nucleotide recorder
There is an urgent need for cancer therapeutics with improved target specificity and novel mechanisms of action. Molecular glues combine the demonstrated capabilities of small molecules as potent drugs with the power of chemically induced proximity. In enabling new protein-protein associations, molecular glues can address many shortcomings of current small molecule cancer therapeutics, which are often limited to protein targets presenting a clear binding pocket. The wide-ranging therapeutic potential of molecular glue has already been recognized; however, to date the discovery of these compounds has been limited to serendipity or the synthesis of bifunctional molecules. In my research, I leverage the recording and reporting power of DNA encoded libraries to deliver a new path to molecular glue discovery. Using a synthetic nucleotide containing a 3’-blocking group, we have made progress toward endowing only molecular glue hits with the ability to be PCR-amplified and sequenced for decoding.
Eric R. King (he/him)
ASTRAZENECA - CHEMISTRY, ONCOLOGY R&D
Metallaphotoredox Catalysis as a Platform for (Trifluoromethyl)thiolation of Aryl- and Alkenyl-Iodides
The trifluoromethylthioether (SCF3) moiety represents a privileged functionality in pharmaceuticals and agrochemistry, however the direct synthesis of aryl- and alkenyl-SCF3 compounds remains comparatively burgeoning. Herein, we have demonstrated a nickel (Ni)-catalyzed, photoredox based approach for the trifluoromethylthiolation of aryl- and alkenyl-iodides to access diverse and biologically relevant SCF3 compounds under mild and air tolerant conditions. The developed methodology tolerates a broad range of substituted (hetero)aromatic aryl- and alkenyl- iodides. The alkenyl-SCF3 products exhibit general Z-selectivity arising from an in-situ photoisomerization mechanism. Moreover, this process could be readily extended to a more general thiolation protocol through the utilization of diverse, medicinally relevant thiols to provide unique alkenyl-sulfide products. The utility of the products is demonstrated via several post-functionalization approaches providing enhanced degrees of molecular complexity in the products.