Programmable therapeutics - Pyrrole-Imidazole Polyamides
Throughout my graduate work in the Dervan Lab, I focused on understanding in vivo selectivity, mechanisms of action, and clinical applicability of DNA-sequence specific small molecule drugs.
Image: A hairpin Py-Im polyamide targeting 5'-WTWCGW-3' DNA sequence. The background shows uptake of compound 3 into U251 tumors.
Originally developed in the Dervan Lab at Caltech, Pyrrole-Imidazole polyamides are sequence specific, cell permeable oligomers that are capable of downregulating gene expression in living cells. We evaluated gene expression effects and biodistribution following polyamide treatment in a mouse model of breast cancer and glioma. Using intravital bioluminescence imaging and next generation mRNA sequencing studies, we discovered that one compound targeted to the Estrogen-Response-Element was capable of downregulating estrogenic gene expression in tumors (1).
For my next project (3), I focused on one of the most critical pathways in cancer – the hypoxic response pathway. Resistance to hypoxia is one of the hallmarks of tumor cells and is one of the major sources of resistance to radiation and chemotherapy. Existing anti-angiogenic therapies, which attempt to starve tumors of their blood supply, can actually make tumors more resistant to hypoxia, thereby promoting tumor progression and metastasis. I attempted to develop an antiangiogenic therapy that does not have this confounding effect. Using a Py-Im polyamide compound targeted to Hypoxia Inducible Factor-1 Response Elements (HRE), I discovered that systemic administration of this compound reduced tumor growth, inhibited blood vessel formation, and sensitized the tumor cells to hypoxia.
This experience was essential in understanding the pros and cons of small molecule drugs over chemogenetics. Chemogenetic approaches can lead to an improved selectivity which is necessary for accurate control of complex systems, such as the brain, which lead me to my postdoctoral project.
1. Nickols NG#, Szablowski JO#, Hargrove AE, Li BC, Raskatov JA, Dervan PB. "Activity of a Py-Im Polyamide Targeted to the Estrogen response Element," Mol. Cancer Ther., 12:675-684, (2013).
2. Raskatov JA, Szablowski JO, Dervan PB, “Tumor Xenograft Uptake of a Py Im Polyamide Varies as a Function of Cell Line Grafted”, J. Med. Chem., 57:8471-8476 (2014)
3. Szablowski JO, Raskatov JA, Dervan PB, “An HRE-binding Py-Im polyamide impairs adaptation of tumors to hypoxia.”, Mol. Cancer Ther., 15 (4), 608-617 (2016) [Research highlights]
4. Yang F, Nickols NG, Li BC, Szablowski JO, Hamilton SR, Meier JL, Wang CM, Dervan PB, “Animal toxicity of hairpin pyrrole-imidazole polyamides varies with the turn unit”, J. Med. Chem., 56 (18), pp 7449–7457 (2013)
5. Mysore VS, Szablowski JO, Dervan PB, Frost PJ, A DNA-binding molecule targeting the adaptive hypoxic response in multiple myeloma has potent in vivo and in vitro anti-tumor effects, Molecular Cancer Research (2016), Mol Cancer Res Published OnlineFirst January 22, 2016