Chemistry and Cancer
22 members representing seven departments at UT Southwestern
The interdisciplinary Chemistry and Cancer (CC) Program is uniquely situated to bridge fundamental biology research with the discovery of novel therapies for the treatment of cancer. CC combines the expertise of synthetic and medicinal chemists, molecular and structural biologists, biochemists, chemical biologists, pharmacologists, and clinician scientists to discover, design, and optimize drug-like small molecules that regulate biological pathways deregulated in cancer. CC’s discovery platform is guided by the hypothesis that an interdisciplinary and chemically focused approach to cancer biology will provide new avenues for discovery in cancer prevention and treatment.
The CC Program is defined by three specific aims: Identification of Molecular Targets of Novel Anti-Cancer Agents; Biochemical Dissection of Regulatory Pathways Relevant to Human Cancer; and Structure-Based Design of Chemicals that Perturb Cancer-Relevant Signaling Pathways.
Identification of Molecular Targets of Novel Anti-Cancer Agents
Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies that specifically target colorectal cancer (CRC), a major priority in our catchment area and the second leading cause of cancer deaths. Mutations in the adenomatous polyposis coli (APC) gene are common in CRC, and more than 90% of those mutations generate stable truncated gene products. Co-leader Jef De Brabander, Ph.D., and Jerry Shay, Ph.D. executed a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein, leading to the identification of a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares cells with wild-type APC.
Biochemical Dissection of Regulatory Pathways Relevant to Human Cancer
Joseph Ready, Ph.D., and Bruce Posner, Ph.D., have established a multi-institute collaboration with Sanford Markowitz, M.D., and Stanton Gerson, M.D., from Case Western, to develop an inhibitor of the prostaglandin-degrading enzyme 15-PGDH for hematological malignancies. This interdisciplinary team of scientists identified a small-molecule inhibitor of 15-PGDH that increases prostaglandin PGE2 levels in bone marrow and other tissues.
Structure-Based Design of Chemicals that Perturb Cancer-Relevant Signaling Pathways
Hypoxia Inducible Factors (HIFs) are heterodimeric transcription factors that are integral to the cellular hypoxic response pathway and sensing oxygen availability. HIFs are also implicated in cancer, which inspired a multi-PI initiative at UTSW to investigate these transcription factors as therapeutic targets. The team of scientists included Co-leader Uttam Tambar, Ph.D., and former program members Richard Bruick, Ph.D.; Kevin Gardner, Ph.D.; and John MacMillan, Ph.D. Although transcription factors are frequently described as 'undruggable' biological targets, scientists at UT Southwestern developed novel chemical strategies to generate artificial ligands that target HIF-2 in an isoform-selective manner.
Courtney, K.D. et al. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2alpha Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol 2018; 36: 867-74. PMCID: PMC5946714.
Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 2017; 356.
Huang, Z. et al. ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc Natl Acad Sci U S A 2018; 115: E9499-E506. PMCID: PMC6176566.
Westover, K.D. et al. Progress on Covalent Inhibition of KRAS(G12C). Cancer Discov 2016; 6: 233-4.
Zeng, M. et al. Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C. Cell Chem Biol 2017; 24: 1005-16 e3.