Updated: September 24, 2015
Stefan Kathman
CBC Scholar: Class of 2014
PhD Candidate, Department of Chemistry, Northwestern University
Advisor: Alexander V. Statsyuk
STATSYUK LAB WEBPAGE
RESEARCH INTERESTS:
Although they are implicated in many cancers, most protein targets in the ubiquitin proteasome system are considered undruggable. However, many of these targets contain essential cysteines which could be inhibited by a covalent drug. The recent FDA approval of afatinib and clinical trial success of ibrutinib have validated cysteine-reactive covalent drugs as cancer therapies. Yet despite the burgeoning interest in covalent drugs, there is no method to systematically screen irreversible inhibitors to identify novel leads. We have developed a general screening method to discover novel cysteine-reactive inhibitors using a fragment-based approach. The key to our method is that it ensures any hits will be selected based on their ability to specifically bind to the protein and not simply due to their greater reactivity. A library of 100 fragments was then screened in batches of ten against the controversial oncoprotein Nedd4-1. There were two hits against Nedd4-1 which were surprisingly not found to inhibit its catalytic cysteine but another essential cysteine. This represents a novel class of inhibitors for a biologically significant target with no tractable small molecule leads. Studies are currently underway to optimize these hits and test their suitability as therapeutics.
PUBLICATIONS:
Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV. A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism. J Am Chem Soc. 2015 Sep 22. [Epub ahead of print] (PubMed)
Kathman SG, Xu Z, Statsyuk AV. A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases. J Med Chem. 2014 Jun 12;57(11):4969-74. (PubMed)
AWARDS:
- The ACS Division of Medicinal Chemistry Predoctoral Fellowship, 2014-2015
- Chicago Biomedical Consortium (CBC) Scholar, 2014-2015
- Chemistry of Life Processes Training Grant (NIH T32 Training Grant for Research at the Chemistry Biology Interface), Northwestern University, 2013
SERVICE:
- Science Club (A weekly outreach program at the Pedersen-McCormick Boys and Girls Club in Uptown that helps Chicago Public Schools students with their science fair projects along with teaching them a hands-on extracurricular science curriculum), Northwestern University, September 2012-present