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Center for Integrative Chemical Biology and Drug Discovery, Dmitri Kireev,

Brittany Jennings
December 6, 2019

Drug discoverers Dmitri Kireev, Ph.D., and Xiaodong Wang, Ph.D., of the UNC Eshelman School of Pharmacy have created a data-driven strategy to be able to treat diseases such as acute myeloid leukemia and nonsmall cell lung cancer.Kireev said controlling which particular members of a large protein family are targeted by a drug is key to achieving an effective therapeutic response in patients, and that’s what they have set out to accomplish.

“Structure-based design is a cornerstone of the modern drug discovery since the 1990s. However, it largely missed the big data revolution. The structure-based approach we propose distills big 3D and chemogenomic data to assemble a small-molecule drug directly inside its protein target,” Kireev said. “It will help to significantly shorten the so-called bench-to-bedside times to better serve the patients with unmet medical needs.”

The technology is based on an original concept of a FRAgment in Structural Environment (FRASE) that helps harness millions of data records from large structural and chemogenomic databases. Several FRASEs extracted from different protein-ligand complexes can be readily combined into a novel ligand for an orphan protein target.

The researchers applied FRASE-based strategy to design anti-tumor agents that selectively target the TYRO3, AXL and MERTK (TAM) family tyrosine kinases. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines.

“Drug selectivity is always challenging due to possible toxicity from unwanted targets,” Wang said. “Our computational-assistant approach will help to achieve the desired selectivity profile of the targeted molecules.”

The researchers, both in the School’s Center for Integrative Chemical Biology and Drug Discovery, recently had their findings published in the Journal of the American Chemical Society.

Veronica Correa
November 27, 2019Dr. Nate HathawayNathaniel Hathaway, Ph.D., a researcher at the UNC Eshelman School of Pharmacy’s Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery and the Lineberger Comprehensive Cancer Center, was published in Nature Biotechnology earlier this month for his work creating tools that can control gene expression.Hathaway, who will be promoted to associate professor Dec. 1, focuses on understanding the mechanisms of gene regulation by chromatin while discovering small molecules that change epigenetic pathways. The Nature Biotechnology publication was a collaboration with other researchers from UNC, a group at Mount Sinai Center for Therapeutics Discovery lead by Dr. Jian Jin, and the Khan research group at National Institutes of Health’s National Cancer Institute.This latest research, titled “Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery,” focused on building a mechanism that could cause dose-dependent gene activation using a combination of protein bioengineering and bifunctional small molecules. The Nature Biotechnology paper is centered around the CRISPR-Cas9 complex, a technology that is used to target different genes by editing the genetic sequence. However, their team used a variant of this technology that does not edit DNA and instead is capable of manipulating the epigenome. There aren’t as many tools that currently focused on dose-dependent gene targeting using proteins that are already expressed in the cell.“What we wanted to do is invent a technology where we could take broadly active inhibitors and repurpose these chemicals focus chromatin regulatory activity to individual genes,” Hathaway said.

Hathaway’s team worked with chemical epigenetic modifiers, which bind to the deactivated Cas9 module while also interacting with molecules involved with epigenetic processes.


Diagram of Chemical Epigenetic Modifiers
Diagram of chemical epigenetic modifiers, courtesy of Nathaniel Hathaway.

Hathaway said the Eshelman Institute for Innovation helped make this project a reality, especially in the early stages. He also said this work had implications in the greater field of epigenetics, or the impacts of gene expression and modification on living things. Multiple cancers and neurological disorders are driven by disruptions in the pathways that control gene expression, so this work has various applications in the field.

In the future, Hathaway wants to improve the method they use to engage target genes, and also to explore new chemistries capable of engaging the dozens of other chromatin regulatory pathways where good inhibitors exist that can be exploited by this approach.

Chemical Biology and Medicinal Chemistry

Brittany Jennings
October 30, 2019

Lindsey Ingerman James, Ph.D., with the UNC Eshelman School of Pharmacy is interested in epigenetic abnormalities that lead to cancer.  For example, misregulation of the NSD2 gene has been implicated in numerous cancers including multiple myeloma and acute lymphoblastic leukemia. NSD2 was further found to be among the most frequently mutated genes across 1,000 pediatric cancer genomes, representing 21 different pediatric cancer subtypes.Over the course of the next five years, James plans to apply medicinal chemistry, chemical biology, and cancer biology approaches to discover first-in-class NSD2 bifunctional degraders in order to better understand NSD2 cancer biology, to assess NSD2 preclinical target validity and as potential therapeutic agents.

To support her work, the National Institutes of Health’s National Cancer Institute recently awarded James with a grant of $1,684,222 over the course of five years.

“Our ultimate goal is to treat human cancers resulting from overexpression of a specific gene, NSD2, by developing molecules that have the unique ability to facilitate the degradation of NSD2. As no such NSD2-targeted therapeutics exist, it is our hope that this would help to address an unmet medical need,” James said.

NC TraCS Institute

Ken Pearce, Albert Bowers and Cyrus Vaziri are working on a pilot project to establish Melanoma Antigen A4 (MAGE-A4, a Cancer/ Testes Antigen) as a new and tractable target for cancer therapy.  The central hypothesis is that MAGE-A4 promotes chemoresistance via activation of the DNA repair protein RAD18. (2017-2018)


Discovery of In Vivo Chemical Probes for Polycomb CBX Domains

Canonoical Polycomb Signaling with Goal of in vivo CBX Antagonists as Chemical Probes of Polycomb FunctionStephen Frye has received funding to develop an in vivo chemical probe of the CBX reader domains of Polycomb repressive complex 1 (PRC1). Chromatin is the complex of histone proteins, RNA, and DNA that efficiently packages the genome within each human cell. The regulation of chromatin accessibility via post-translational modifications (PTM) of histones is of great current interest as opportunities for pharmacological intervention in the ‘writing’, ‘reading’ and ‘erasing’ of these PTMs are significant. The biological consequences of most PTMs result from their recruitment of regulatory machinery via protein-protein interactions directly facilitated by the PTM. The binding domains involved in PTM recognition on chromatin are referred to as “readers”.

The overarching objective of this program is to develop an in vivo chemical probe of the CBX reader domains of Polycomb repressive complex 1 (PRC1). There are eight human CBX chromodomains that function as methyl-lysine (Kme) recognition domains (readers) within the two major chromatin repressive complexes that are conserved across higher eukaryotes. CBX proteins 1, 3 and 5 are associated with the heterochromatin protein 1 (HP1) complex. Their Kme binding activity is required for compaction and repression of chromatin that bears the histone H3, lysine 9 trimethyl (H3K9me3) mark. CBX proteins 2, 4, 6, 7, and 8 are associated with the PRC1 which binds the H3K27me3 mark. As appropriate repression of genomic loci is critical throughout organismal development and differentiation, dysregulation of HP1 and Polycomb pathways is implicated in many disease states and an in vivo chemical probe targeting PRC1 would be a first-in-class agent targeting a pathway of high disease relevance and would also represent a unique tool to explore Polycomb biology in complex in vivo systems.

The deliverable from this effort will be a high-quality in vivo chemical probe, freely available to the academic community, with confirmed activity and well characterized mechanism versus the CBX readers of PRC1 to catalyze progression of this target toward new therapeutic discoveries in oncology and, potentially, other diseases.


The Application of Enhanced Cavitation to Enable DNA and Chromatin Extraction from Archived Tissues.

National Cancer Institute Innovative Molecular Analysis Technologies Program R33, Samantha Pattenden with Paul Dayton (Biomedical Engineering) and Ian Davis (Genetics, Pediatric Hematology/Oncology)

Formalin-fixed paraffin embedded (FFPE) patient biopsy samples are an important source of tumor tissue for cancer research and diagnostics.  There is considerable interest in expanding the use of FFPE tissue to include epigenetic cancer signatures, which are heritable changes not associated with alteration in DNA sequence.  We have invented a chemically inert reagent based on a metastable perfluorocarbon nanodroplet that our preliminary data indicate can be used to enhance and simplify processing of FFPE tissue for epigenetic analyses, including cancer diagnostics.  We will explore and optimize aspects of this novel approach, with a goal towards commercial translation.

NIH/NIGMS R01Methyl-lysine Reader Families: Target Class Strategy

Discovery of Chemical Probes for Chromatin Readers

Stephen Frye, PhD has received funding for Discovery of Chemical Probes of Chromatin Readers.  The over-arching objectives of this program are to develop chemical problems of chromatin reader domains that exploit three distinct mechanisms of molecular recognition: 1) reader domains that function as dimers; 2) reader domains that operate via a dynamic, induced-fit recognition mechanism; and 3) multivalent reader domains. This program builds on research that was initially funded by NIH in 2019 under the American Recovery and Reinvestment Act (ARRA Challenge Grant) for Discovery of Small Molecule MBT Domain Antagonists and a subsequent R01 for Discovery of Chemical Probes for Methyl-Lysine Readers.


Microbiome-Targeted Probes to Eliminate Chemotherapy-Induced GI Toxicity.

Stephen Frye, PhD and Lindsey James, PhD will collaborate with PI Matt Redinbo, PhD on his R01 grant from NCI entitled Microbiome-Targeted Probes to Eliminate Chemotherapy-Induced GI Toxicity.  The overarching hypothesis is that microbial enzymes expressed by the GI microbiome can be inhibited using targeted small molecules to prevent the unwanted reactivation of potent antineoplastic drugs in the intestinal lumen.  Redinbo is a Distinguished Professor of Chemistry with joint appointments in the Departments of Biochemistry  and Microbiology in the School of Medicine.