Chemistry and Cancer


The design and use of small drug-like molecules and associated molecular probes to discover, interrogate, and target biological pathways relevant to cancer.


Immunohistochemistry of breast tumor sections
Immunohistochemistry of breast tumor sections, arranged in tissue microarray format, shows ACSS2 protein expression (bottom row depicts noncancerous tissue samples). By capturing acetate as a carbon source, ACSS2 can help fuel tumor growth (see Comerford et al., 2014).

The Chemistry and Cancer Program combines the expertise of synthetic and medicinal chemists, molecular biologists, biochemists, structural biologists, and clinician-scientists to discover, design, and optimize drug-like small molecules that regulate biological pathways deregulated in cancer. The Program engages 19 members drawn from six departments on campus.

The program’s discovery process takes one of two approaches. For a chemistry-to-biology approach, discovery starts by identifying natural or unnatural small molecules that are selectively lethal to human cancer cell lines, then determining exactly how the small molecules have their effect. In a biology-to-chemistry approach, hypotheses regarding the “druggability” and cancer relevance of specific biological pathways investigated by Cancer Center scientists can be tested with drug-like chemicals.


  • Molecular targets of cancer cell–specific small-molecule toxins
  • Novel, cancer cell–specific pathways
  • Proof-of-concept preclinical development of cancer cell–specific small-molecule toxins
  • The hypoxia response pathway

Research Highlights

The molecular structure of discoipyrrole A
The molecular structure of discoipyrrole A (see Hu et al., 2013).

Center for High-Throughput Functional Annotation of Natural Products (HiFAN). Supported by nearly $1.5 million from the National Institutes of Health, Simmons Cancer Center investigators (with collaborators at Simon Fraser University) are developing an innovative research paradigm to characterize the mechanisms of action of natural products and botanicals more quickly and precisely. The approach incorporates natural products chemistry, biological screening, data analytics, and bioinformatics, combining two high-throughput platforms (cytological profiling and a technique called FUSION, developed at UT Southwestern) to discern in greater detail the impact on cells of both complex chemical mixtures and pure natural compounds. The project also will develop a data-driven website to make findings available widely within the scientific community.


Small molecule disrupters
Tucked in the cavity found within a portion of the HIF-2α molecule called the PAS-B domain are two different small molecule disrupters of HIF-2 (see Scheuermann et al. 2013, Scheuermann et al. 2015).

HIF-2α and kidney cancer. More than a decade of research by Simmons Cancer Center biochemists, biophysicists, and chemists has elucidated the workings of hypoxia inducible factor-2α, a master regulator that responds to changes in tissue oxygen levels encountered by tumors and determines whether genes that help cancer cells survive and proliferate are activated downstream. HIF-2α, once considered “undruggable,” has been implicated in development and progression of several types of cancer. Now, the first HIF-2α antagonist to enter clinical development, a Peloton Therapeutics drug candidate called PT2385, is in early patient trials at UT Southwestern. Preclinical work has shown that PT2385 can suppress gene expression that fuels tumor growth, progression, and blood vessel development in some kidney cancers.

To Get Involved

Program meetings are held every other Friday morning. The Program seeks additional physicians and scientists having both broader and deeper understanding of human cancer to further collaboration of new scientific directions for high-throughput screening assays, medicinal chemistry projects, and new natural product opportunities.

Contact Dr. De Brabander for more details about the Chemistry and Cancer Program, meetings, and more.

Selected Publications

Chau, V. et al. Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res 74, 586-597 (2014).

Choi, C. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18, 624-629 (2012).

Comerford, S.A. et al. Acetate dependence of tumors. Cell 159, 1591-1602 (2014).

Ding, M. et al. Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling. Nat Cell Biol 18, 319-327 (2016).

Fisher, K.W. et al. AMPK promotes aberrant PGC1beta expression to support human colon tumor cell survival. Mol Cell Biol 35, 3866-3879 (2015).

Fu, P. et al. Carpatamides A-C, cytotoxic arylamine derivatives from a marine-derived Streptomyces sp. J Nat Prod 77, 1245-1248 (2014).

Garcia-Rodriguez, J. et al. Synthesis and structure-activity studies of the V-ATPase inhibitor saliphenylhalamide (SaliPhe) and simplified analogs. Bioorg Med Chem Lett 25, 4393-4398 (2015). 

Guo, Y. et al. Regulating the ARNT/TACC3 axis: multiple approaches to manipulating protein/protein interactions with small molecules. ACS Chem Biol 8, 626-635 (2013).

Hu, Y. et al. Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis. J Am Chem Soc 135, 13387-13392 (2013).

Hunter, J.C. et al. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc Natl Acad Sci USA 111, 8895-8900 (2014).

Jat, J.L. et al. Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins. Science 343, 61-65 (2014).

Jiao, L. and Liu, X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science 350, aac4383 (2015).

Kilgore, J.A. et al. Identification of DNMT1 selective antagonists using a novel scintillation proximity assay. J Biol Chem 288, 19673-19684 (2013).

Kim, H.S. et al. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155, 552-566 (2013).

Kulak, O. et al. Disruption of Wnt/beta-catenin signaling and telomeric shortening are inextricable consequences of tankyrase inhibition in human cells. Mol Cell Biol 35, 2425-2435 (2015).

Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155, 1049-1060 (2013).

Laxman, S. et al. Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites. Sci Signal 7, ra120 (2014).

Li, N. et al. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth. Genes Dev 29, 157-170 (2015).

Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014).

Orvedahl, A. et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480, 113-117 (2011).

Partch, C.L., Gardner, K.H. Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proc Natl Acad Sci USA 108, 7739-7744 (2011).

Potts, M.B. et al. Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B. Nat Chem Biol 11, 401-408 (2015).

Potts, M.B. et al. Using functional signature ontology (FUSION) to identify mechanisms of action for natural products. Sci Signal 6, ra90 (2013).

Rogers, J.L. et al. Development of inhibitors of the PAS-B domain of the HIF-2alpha transcription factor. J Med Chem 56, 1739-1747 (2013).

Scheuermann, T.H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9, 271-276 (2013).

Sengupta, S. et al. Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proc Natl Acad Sci USA 110, 18826-18831 (2013).

Skrypnyk, N. et al. PPARα activation can help prevent and treat non-small cell lung cancer. Cancer Res 74, 621-631 (2014).

Sun, Q. et al. Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci USA 110, 1303-1308 (2013).

Wang, Z. et al. Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway. J Biol Chem 289, 31950-31959 (2014).

Zhang, Y. et al. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 348 (6240), aaa2340  (2015).