Chemical Biology and Drug discovery

Our lab is interested in chemical biology and drug discovery with a focus on the apoptosis pathway. Using automated and robotic equipment we screen chemical and siRNA libraries to identify chemical and genetic probes and use them as tools to better understand biological pathways with a focus on apoptosis and the pathogenesis of leukemia.

For example, to identify small molecule inhibitors of the anti-apoptotic protein XIAP, a million compound small molecule library was screened. From this screen, small molecule XIAP inhibitors were identified and subsequently used as tools to validate XIAP as a therapeutic target in acute leukemia. Based partly on this work, a clinical trial of XIAP antisense oligonucleotides in combination with reinduction chemotherapy was
launched in patients with refractory acute myeloid leukemia. Similar chemical biology approaches have been used to identify small molecules that sensitize resistant cells to death receptor ligands by reducing expression of the caspase-8 inhibitor FLIP. Our work on small molecules that decrease FLIP and activate the death receptor pathway of caspase activation also led to a clinical trial of the synthetic triterpenoid CDDO in patients with refractory leukemia.

Finally, efforts are underway to advance novel molecules from the lab to the bedside. Here, off-patent drugs are screened to identify compounds that impact targets important in the pathogenesis of malignancy and thus have previously unrecognized anti-cancer activity. Through this approach, new insights into molecular pathways are gained. In addition, these old drugs can be “repurposed” and moved rapidly into clinical trial for the treatment of malignancy.

Graduate Students:

• Kika Anyiwe
• Reza Beheshti-Zavareh
• Craig Simpson
• Amanda Wasylishen

Selected References:

• BZ Carter, M Gronda, Z Wang, K Welsh, C Pinilla, M Andreeff, W Schober, A Nefzi, GP Pond, IA Mawji, RA Houghten, J Brandwein, MD Minden, A Schuh, RA Wells, H Messner, K Chun, JC Reed, AD Schimmer. Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of leukemia cell lines and patient samples. Blood, 2005 105: 4043-50

• IA Mawji, CD Simpson, R Hurren, M Gronda, MA Williams, J Filmus, J Jonkman, R Da Costa, B Wilson, MP Thomas, JC Reed, GV Glinsky, AD Schimmer. Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation. Journal of the National Cancer Institute, 2007, 99: 811-822

• IM Mawji, CD Simpson, M Gronda, MA Williams, R Hurren, C Henderson, A Datti, JL Wrana, AD Schimmer. A chemical screen identifies anisomycin that sensitizes resistant cells to anoikis by decreasing FLIP protein synthesis. Cancer Research. 2007, 67:8307-15