Chemistry and Cancer
Mission
The design and use of small drug-like molecules and associated molecular probes to discover, interrogate, and target biological pathways relevant to cancer.
Overview
The Chemistry and Cancer Program combines the expertise of researchers including 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 more than two dozen members drawn from a range of departments and centers 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.
Themes
- 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
Center for High-Throughput Functional Annotation of Natural Products (HiFAN). Supported by nearly $1.5 million from the National Institutes of Health, Simmons Comprehensive 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.
- Selected citation: 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).
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.
- Selected citation: Scheuermann, T.H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9, 271-6 (2013).
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 advance collaboration in 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. jef.debrabander@utsouthwestern.edu
Selected Publications
Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112-7 (2016).
Cho, H. et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature 539, 107-11 (2016).
Dutchak, P.A. et al. Regulation of hematopoiesis and methionine homeostasis by mTORC1 inhibitor NPRL2. Cell Rep 12, 371-9 (2015).
Feng, Y. et al. Rifamycin biosynthetic congeners: isolation and total synthesis of rifsaliniketal and total synthesis of salinisporamycin and saliniketals A and B. J Am Chem Soc 138, 7130-42 (2016).
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).
Gazdar, A.F. et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 10, 553-64 (2015).
Gibson, B.A. et al. Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science 353, 45-50 (2016).
Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).
Han, T. et al. The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α. Nat Chem Biol 12, 511-5 (2016).
Hwang, S.Y. et al. Direct targeting of β-catenin by a small molecule stimulates proteasomal degradation and suppresses oncogenic Wnt/β-catenin signaling. Cell Rep 16, 28-36 (2016).
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/β-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).
Meyer, C.J. et al. Peloruside A inhibits growth of human lung and breast tumor xenografts in an athymic nu/nu mouse model. Mol Cancer Ther 14, 1816-23 (2015).
Moon, J. et al. Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist. Proc Natl Acad Sci 114, 1649-54 (2017).
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).
Rujirawanich, J. et al. Synthesis and biological evaluation of kibdelone C and its simplified derivatives. J Am Chem Soc 138, 10561-70 (2016).
Scheuermann, T.H. et al. Isoform-selective and stereoselective inhibition of hypoxia inducible factor-2. J Med Chem 58, 5930-41 (2015).
Shi, H. et al. Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING. Proc Natl Acad Sci 112, 8947-52 (2015).
Theodoropoulos, P.C. et al. Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat Chem Biol 12, 218-25 (2016).
Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci 114, 1637-42 (2017).
Xiang, S. et al. The LC domain of hnRNPA2 adopts similar conformations in hydrogel polymers, liquid-like droplets, and nuclei. Cell 163, 829-39 (2015).
You, L. et al. Development of a triazole class of highly potent Porcn inhibitors. Bioorg Med Chem Lett 26, 5891-5 (2016).
Zhang, L. et al. Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer. Sci Transl Med 8, 361ra140 (2016).
Zhang, Y. et al. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 348 (6240), aaa2340 (2015).