^{Chemical Biology and Therapeutics}

Chemistry Centers

Acquire, develop, and deploy state-of-the-art chemistry capabilities to advance research at St. Jude towards the discovery of breakthrough treatments for catastrophic pediatric illnesses.

About the Centers

The CBT Chemistry Centers consist of three highly integrated centers that collectively provide state-of-the-art chemical probe design, synthesis, and evaluation of capabilities to support research at St. Jude.

The Chemistry Centers routinely assist collaborators by coordinating work with other CBT centers, providing training, consultation, and help with defining project strategy, writing grant applications, patents, and manuscripts for publication. Our projects are generally highly collaborative, involving an iterative exchange of material and data with research labs that often last months, if not years.

Chemical Biology Center

Chemical Biology Center (CBC) applies advanced chemical biology methods to develop sophisticated chemical tools designed to map and interrogate disease-related biological pathways. The CBC chemical toolbox includes PROTACs, molecular glues, pull-down, photoaffinity, and imaging probes. The center has experience developing and utilizing biochemical assays, including fluorescence polarization (FP), time-resolved fluorescence energy transfer (TR-FRET), AlphaScreen, and cell-based assays such as CellTiter-Glo, Caspase-Glo, and alamarBlue.

We reach out to researchers and ask, 'What do you think of this target? Do you think it's druggable? Can we find a small molecule? Can we find a chemical probe?' We're here to support and collaborate with the researchers within St. Jude and other PIs that have expertise in biology or pharmacology that don't have the expertise in chemistry or chemical probe discovery.

Gisele Nishiguchi, CBC Lead Scientist

Medicinal Chemistry Center

Medicinal Chemistry Center (MCC) focuses on identifying and developing potent and selective small molecules to investigate disease-related biological targets in cells and in vivo preclinical models. Typically, the center would help researchers to find relevant literature disclosed probes (conferences, scientific journals, or patents) and arrange for their purchase or synthesis if commercially unavailable. In addition, the center would engage in a hypothesis-driven research effort to provide novel chemical probes for targets where such molecules do not exist. MCC would facilitate forming multidisciplinary projects, including core teams, multiple PIs, and other collaborative centers for these efforts. 

Our team will drive the projects from hit generation and validation (e.g., HTS, fragment screening, rational design) through lead optimization relying on structure-based drug discovery, chemoinformatics, and ADME data, to delivering robust in vitro/ in vivo chemical probes. 

Getting a hit is just the beginning of the process. Most compounds have to be optimized further to show any sort of activity, so you really have to commit yourself to the long game if you're going to look for new chemical matter. We constantly ask ourselves, 'Is this the best molecule we can make, or is there something we can do to improve it?'

Brandon Young, MCC Lead Scientist

Analytical Technologies Center

Analytical Technologies Center (ATC) provides an extensive battery of assays designed to evaluate compound chemical, biophysical and ADME properties. These include sample purity and integrity, aqueous solubility, permeability, microsomal and plasma stability, simulated gastric fluid (SGF) stability, PBS stability, plasma/tissue protein binding, and P-gp/BCRP efflux, as well as in vivo pharmacokinetic parameters such as drug plasma and brain unbound concentrations. The center also develops highly customized bioanalytical methods, formulations for in vivo studies, mass spectrometry-based biochemical assays, and tissue imaging. In addition, the center has extensive experience in natural product extract fractionation, high throughput library purification, and structure determination.

ATC generally provides high throughput analytical support to researchers and investigators in CBT and across the campus, depending on the lab's requirements. Working in ATC has indulged me with a broad experience in translational research. I became familiar with the entire drug discovery process from synthesis to screening, to preclinical studies.

Divyabharathi Chepyala, Senior Researcher

Publications

Evaluating and evolving a screening library in academia: the St. Jude approach

Nishiguchi G et al. Drug Discov Today, 2021

Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators

Nishiguchi G et al. J Med Chem, 2021

Practical approaches to evaluating and optimizing brain exposure in early drug discovery

Freeman BB et al. Eur J Med Chem, 2019

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

Chang Y et al. Blood 2021

Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases.

Yang SW et al. Nat Commun, 2020

About the Director

Zoran received his Ph.D. in organic chemistry in 1995 from the University of Leeds, UK. That same year he joined Organon UK and then continued his medicinal chemistry and drug discovery career as medicinal chemistry director and research fellow within Schering-Plough, Merck, and Eli Lilly. Over this period, Zoran has been fortunate to contribute to and direct teams that delivered multiple clinical candidates over a range of therapeutic areas, including neuro-oncology, neurodegeneration, psychiatry, and pain. In the process, he has authored >80 peer-reviewed publications, patents, book chapters and edited two books on drug discovery topics. Zoran served on various drug discovery committees and advisory boards, most recently the Steering Committee of the AARC Chemistry in Cancer Research and Scientific Committee for the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference. Since joining St. Jude in October 2016, Zoran’s research focus includes developing small molecule protein degraders and epigenetic modulators for the treatment of pediatric cancers such as medulloblastoma, neuroblastoma, acute lymphoblastic, and myeloid leukemia.

Zoran Rankovic Bio