Our lab is fundamentally interested in understanding, from a structural and biophysical perspective, the functioning of proteins involved in regulating transcription, particularly those involved in the dysregulation associated with the development of cancer. Structural and functional characterization of the native forms of these proteins and their relevant complexes via NMR spectroscopy, X-ray crystallography, and a variety of other techniques provides a baseline of understanding. Subsequent characterization of the oncoprotein forms then provides a detailed understanding of the molecular mechanism of oncogenesis associated with altered forms of these proteins. Such knowledge leads to novel avenues for the design of therapeutic agents to treat the cancers associated with these particular oncoproteins.
One current focus is structural studies of a novel transcription factor referred to as the core-binding factor (CBF). This heterodimeric protein is essential for hematopoietic development. Gene translocations associated with the genes coding for the two subunits of CBF produce novel fusion proteins which have been implicated as playing a role in more than 30% of acute leukemias. We have carried out structural (NMR spectroscopy and X-ray crystallography) and functional studies of the oncoprotein forms of the two subunits of CBF that are associated with leukemia to gain an understanding of their roles in the development of leukemia. Another focus area is on fusion proteins involving the transcription factor MLL, which are implicated in a high percentage of pediatric leukemias. We also have an effort focused on the transcription factor ERG which has a critical role in leukemia as well as prostate cancer.
Our chemical biology efforts focus on the development of highly targeted small molecule inhibitors of the oncoprotein forms of CBF and MLL. Using structural information on the proteins, various screening approaches, NMR and fluorescence-based assays, and medicinal chemistry, we have developed the first small molecule inhibitors of these proteins. This is a collaborative effort with outside investigators at the University of Pennsylvania, University of Massachusetts, Cornell, and Loyola University. As these are transcription factor targets which have been viewed as “undruggable," our successful development of inhibitors targeting them is opening up new avenues for drug development.
A third focus for the lab has been the application of solution NMR methods to the structure determination of membrane proteins. The vast majority of drug targets are membrane-embedded proteins. This class of proteins has presented significant challenges for structure determination by any method. We completed the structure determination of the largest helical membrane protein to be solved by NMR spectroscopy at the time. This structure established a paradigm for determining structures of this class of proteins by solution NMR. We are currently examining additional technical improvements in this area as well as targeting new systems for structure determination.
- Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. Illendula A., Gilmour J., Grembecka J., Tirumala VSS, Boulton A, Kuntimaddi A., Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, and Bushweller JH. EBioMedicine. 8: 117-131 (2016). Pubmed PMID: 27428424; PubMed Central PMCID: PMC4919611
- Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH. Science. 347(6223):779-84 (2015). PubMed PMID: 25678665; PubMed Central PMCID: PMC4423805
- Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential. Kuntimaddi A, Achille NJ, Thorpe J, Lokken AA, Singh R, Hemenway CS, Adli M, Zeleznik-Le NJ, Bushweller JH. Cell Reports. 11(5):808-20 (2015). PubMed PMID: 25921540; PubMed Central PMCID: PMC4426023.
- Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited. Regan MC, Horanyi PS, Pryor EE Jr, Sarver JL, Cafiso DS, Bushweller JH. Proc Natl Acad Sci U S A. 110:13374-9 (2013)
- MLL fusion partner AF9 is an intrinsically disordered transcriptional regulator which recruits multiple partners via coupled folding and binding. Leach BI, Kuntimaddi A, Schmidt CR, Cierpicki T, Johnson SA, and Bushweller JH. Structure, 21:176-83 (2013). PubMed PMID: 23260655. PubMed PMCID: PMC3545106.
B.A. Dartmouth College, 1984
Ph.D. University of California, Berkeley, 1989
NIH Postdoctoral Fellow, ETH-Zurich, Switzerland,1990-1992