Research

Overview: Studying/Targeting Advanced Lung Cancer and Cancer-Related Pain

Our research is focused on harnessing chemical biology and medicinal chemistry approaches for the development of chemical tools and drug candidates that target Na_V as well as TRP ion channels involved in pain signaling and antioxidant proteins involved in H₂O₂ signaling as well as ferroptosis in advanced states of Non-Small Cell Lung Cancer (NSCLC). Our expertise encompasses reversible, covalent and photoswitchable chemical probes which are employed to study the underlying biological mechanisms tied to their activity. The key enabling technologies of our group are a (chemo)proteomics analyses platform to study protein targets, off-target engagement as well as mechanisms-of-action for small molecules and a semi-automated high-throughput experimentation (HTE) platform to perform chemical reactions at an accelerated pace.

Overview of the research topics pursued by the Konrad laboratory, divided into biology research, specifically cancer cell biology and (chemo)proteomics, and chemistry research, specifically medicinal chemistry and chemical methodology development.

Uncovering and Harnessing New Vulnerabilities for the Treatment oder Advanced Cancers

A focus of our research is establishing chemical methodologies that allow the synthesis and modification of new chiral drug scaffolds. These scaffolds are employed in covalent fragment-based screenings that combine phenotypic analysis in NSCLCs with the mass spectrometry-based chemical proteomics method Activity-Based Protein Profiling (ABPP). ABPP, in general, allows the analysis of a reaction between a chemical probe and a whole proteome. This approach enables the expedient identification of the protein targets of our small molecule scaffolds that lead to the observed phenotype in NSCLCs. The compounds serve as chemical tools to uncover the mechanisms as well as pathways that are associated with their target proteins and can be advanced into drug candidates by using medicinal chemistry. It is worth noting that the great potential of ABPP includes furnishing global structure-activity relationships (SARs), i.e. for all detectable proteins within the evaluated proteomes in parallel. This feature allows to assess and optimize multiple parameters of the drug candidates, such as the affinity for the desired protein as well as for the off-targets, simultaneously. In addition, if substitution patterns that are incorporated into the scaffolds do not benefit the affinity to the target binding pocket, ABPP will provide insights into which proteins are susceptible to the evaluated substituents. Our approach to develop a broad library of drugs candidates is motivated by the diversity of NSCLC genotypes. The availability of an arsenal of drugs that target different cancer pathways is a first step towards personalized and precise cancer treatments.

Overview of a phenotypic screening approach used in the Konrad laboratory to identify covalent small molecules with a specific activity in advanced lung cancer states followed by uncovering the phenotype-producing target protein via chemoproteomics analysis.

Inducing Ferroptotic Cell Death in Lung Cancers

Advanced drugs that are approved for the treatment of NSCLC, such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) stall cancer progression by blocking angiogenesis and migration. Since the cancer cells remain alive, however, they can gradually develop resistances to the inhibitors. Therefore, it would be highly desirable to develop pharmaceutical agents that directly induce cell death to circumvent this adaptive mechanism. In contrast to induction of apopotosis, which is frequently suppressed in cancers, a cell death mechanism that remains active in many cases and thus creates a vulnerability is the ferroptotic pathway. To harness the induction of ferroptosis towards cancer treatment, we are developing chemical probes that allow us to study mechanisms that are associated with this unusual oxidative cell death pathway and use medicinal chemistry to advance these tools into drug candidates.

Chemical Reactions for Therapeutic Interventions

The site-selective functionalization of amino acid residues on a native protein within the human proteome is one of the most significant challenges in organic chemistry and chemical biology. This challenge is met in the development of reactivity-based therapeutics, such as covalent inhibitors. Covalent inhibitors contain carefully designed ligand structures that reversibly bind to a targeted protein site. In contrast to traditional drugs, they are additionally equipped with an electrophilic functionality (named ‘chemotype’ or ‘warhead’) that reacts with a defined amino acid residue in proximity to the binding site and thereby irreversibly modifies the protein-of-interest. To date, only a small set of reliable, stable and selective chemotypes are available. A prominent example is acrylamide, which selectively reacts with the highly nucleophilic cysteine and selenocysteine residues. Based on this discovery, a new class of covalent anticancer drugs has emerged which recently entered the pharmaceutical market. Afatinib, for instance, is a covalent tyrosine kinase inhibitor which is used for the treatment of NSCLC. Our research aims to design electrophiles that enable reliable and selective reactions with specific amino acids to form stable covalent bonds as basis for the development of new classes of reactivity-based therapeutics.

Schematic depiction of an covalent small molecule with a reactive element, also named warhead, which can either engage a cysteine or lysine side chain on the target protein.