About
Overview
The Soellner laboratory is devoted to the study of cancer pharmacology. Specifically, we aim to develop novel therapeutics and use these inhibitors to understand oncogenic signaling in breast cancer. My laboratory routinely performs organic synthesis, medicinal chemistry optimization, and biochemical and cellular evaluations (including microscopy and flow cytometry) of potential therapeutics.
My laboratory works on fundamental and applied approaches to: (a) Identify mechanisms that modulate kinase conformation, (b) Explore stabilizing kinase conformations with small molecules, and (c) Utilize these finding to generate selective inhibitors that can stabilize particular protein conformations for improved signaling inhibition. Towards these goals, we have developed a robust ‘selective proteolysis’ methodology that can identify changes in protein kinase conformation. Further, we are developing kinase inhibitors that stabilize various global conformations of these kinases to interrogate how modulating both catalytic and scaffolding functions can be utilized as a novel approach for targeting the kinome.
Major Research Themes
- High quality, selective kinase inhibitors made freely available to the science community. Pharmacological approaches to studying kinases are attractive, however, these experiments require highly selective inhibitors. Unfortunately, few truly selective kinase inhibitors have been reported. My lab reported the first highly selective inhibitors for c-Src kinase, a kinase involved in many important and diverse oncogenic processes. Significantly, my lab has made each of our selective kinase inhibitors available free of charge. In addition, several of our inhibitors are commercially available. Our selective kinase inhibitors have made a large impact on the study of c-Src kinase in biological systems.
Representative Publications:
Development of a highly selective c-Src kinase inhibitor. Kristoffer R. Brandvold, Michael E. Steffey, Christel C. Fox, and Matthew B. Soellner (2012). ACS Chemical Biology 7, 1393–1398. PMCID: PMC3423592.
Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine. Frank E. Kwarcinski, Christel C. Fox, Michael E. Steffey, and Matthew B. Soellner (2012). ACS Chemical Biology 7, 1910–1917. PMCID: PMC3500393.
Exquisitely specific bisubstrate inhibitors of c-Src kinase. Kristoffer R. Brandvold, Shana M. Santos, Meghan E. Breen, Eric J. Lachacz, Michael E. Steffey, and Matthew B. Soellner (2015). ACS Chemical Biology 10, 1387–1391.
- Biological evaluation of potential therapeutics for TNBC. Triple-negative breast cancer is an aggressive form of breast cancer for which there is no approved targeted therapy. My lab has explored the application of kinase inhibitors, especially inhibitors of c-Src kinase, in triple-negative breast cancer and we have elucidated signaling pathway changes resulting from inhibition of key kinases. In addition, we have explored the utility and mechanisms of natural products as potential TNBC therapeutics.
Representative Publications:
Development of a highly selective c-Src kinase inhibitor. Kristoffer R. Brandvold, Michael E. Steffey, Christel C. Fox, and Matthew B. Soellner (2012). ACS Chemical Biology 7, 1393–1398. PMCID: PMC3423592.
Irreversible inhibitors of c-Src kinase that target a nonconserved cysteine. Frank E. Kwarcinski, Christel C. Fox, Michael E. Steffey, and Matthew B. Soellner (2012). ACS Chemical Biology 7, 1910–1917. PMCID: PMC3500393.
Synthesis and biological evaluation of lactimidomycin and its analogues. Brian J. Larsen, Zhankui Sun, Eric Lachacz, Yaroslav Khomutnyk, Matthew B. Soellner*, and Pavel Nagorny* *co-corresponding authors (2015). Chemistry: A European Journal 21, 19159–19167.
Molecular determinants of drug response in TNBC cells. Nathan M. Merrill, Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, LiWei Bao, John P. Lloyd, Joel A. Yates, Aki Morikawa, Sofia D. Merajver and Matthew B. Soellner (2019). Breast Cancer Research & Treatment doi: 10.1007/s10549-019-05473-9.
- Methodologies to design novel kinase inhibitors. Protein kinases play a key role in cell signaling and regulation of biological processes such as proliferation, differentiation, and apoptosis. More than 160 protein kinases have been implicated in disease, including cancer. In light of this, kinases are highly attractive targets for drug development. Despite the large number of potential targets, all clinically-used kinase inhibitors address only a handful of well-known kinases. My lab has developed methodologies that can be adapted to target any kinase of interest to generate inhibitors with high specificity. Our technologies enable identification of inhibitors for a wider breadth of kinase targets than existing strategies have yielded.
Representative Publications:
Activation state-selective kinase inhibitor assay based on ion mobility-mass spectroscopy. Jessica N. Rabuck, Suk-Joon Hyung, Christel C. Fox, and Matthew B. Soellner*, and Brandon T. Ruotolo* *co-corresponding authors (2013). Analytical Chemistry 85, 6995–7002. PMCID: PMC3784979.
Development of a chimeric c-Src kinase and HDAC inhibitor. Kristin S. Ko, Michael E. Steffey, Kristoffer R. Brandvold, and Matthew B. Soellner (2013). ACS Medicinal Chemistry Letters 4, 779–783. PMCID: PMC3763859.
Substrate activity screening for kinases: Discovery of small molecule substrate-competitive c-Src inhibitors. Meghan E. Breen, Michael E. Steffey, Eric J. Lachacz, Frank E. Kwarcinski, Christel C. Fox, and Matthew B. Soellner (2014). Angewandte Chemie 53, 7010–7013. PMCID: PMC4108202.
Discovery of bivalent kinase inhibitors via enzyme-templated fragment elaboration. Frank E. Kwarcinski, Michael E. Steffey, Christel C. Fox, and Matthew B. Soellner (2015). ACS Medicinal Chemistry Letters 6, 898–901.
