Prof. Dr. Dennis Gillingham Department of Chemistry Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 13 foundShow per page10 10 20 50 Transfidelity Research Project | 1 Project MembersImported from Grants Tool 4718138 Exploring DNA encoded library technology against cell surface targets Research Project | 1 Project MembersImported from Grants Tool 4708804 A novel DNA encoded library selection method for identifying binders and their affinity to targets Research Project | 1 Project MembersImported from Grants Tool 4699612 Novel Payloads for Antibody Drug Conjugates used for Cancer Therapies Research Project | 1 Project MembersImported from Grants Tool 4699776 Amplifying information on binding and function from DNA encoded collections of small molecules Research Project | 1 Project MembersNo Description available ExploDProteins Research Project | 1 Project MembersHere I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translational possibilities in cancer. Cancer cells are often acutely sensitive to DNA damage because they have one or more faulty DNA damage response pathways - a feature that makes them highly dependent on their remaining DNA repair systems. We will pioneer two novel and related chemical approaches for selectively degrading proteins by modulating DNA damage response pathways with bifunctional DNA damaging molecules. We will do this by reprogramming E3 ligases. E3 ligases are multi-protein complexes that catalyse the formation of polyubiquitin chains on its substrates, leading to their degradation in the protein recycling station known as the proteasome. A recent revolutionary advance in chemical biology is to use small molecules to change the specificity of E3 ligases, leading to the degradation of user-defined proteins. By degrading proteins instead of inhibiting them, these small molecules achieve levels of functional modulation typically only possible with genetic techniques. We are inspired by this new protein degradation technology, but will take it in a new direction. Chemical damage of DNA recruits E3 ligases as well as critical DNA damage response proteins in preparation for DNA repair. We will invent a new generation of small molecule protein degradation catalysts and reagents by repurposing these natural responses to DNA damage. We will accomplish our goal with three aims: Aim 1: Use DNA damage as a homing signal for induced protein degradation Aim 2: Use direct repair of DNA damage by the repair protein methylguanine methyltransferase (MGMT) to promote the degradation of other proteins Aim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damage I propose an ambitious project that will create conceptually novel ways to study the DNA damage response and potentially build new medicines. Targeting DNA Replication Stress through Novel Small-Molecule Degraders in Cancer Research Project | 3 Project MembersNo Description available Formyl- and acylborylation of alkynes to unlock the potential of boron heterocycles in drug discovery Research Project | 1 Project MembersNo Description available Chemical Tailoring of RNAs and Vesicles to Create New Drugs Research Project | 1 Project MembersRNA therapeutics suffer from stability, immunogenicity, and delivery problems. We will take inspiration from two recent discoveries in biology to help us build better RNA therapeutics: 1. Methylated RNAs are substrates for direct reversal repair enzymes and their methylation state controls their function; 2. Exosomes are natural delivery systems for RNAs of all sizes. The fact that Nature uses alkyl groups to control the function of RNAs suggests that chemists could too. I will study which alkyl groups on RNA get repaired, and which do not, facilitating the design of RNAs with alkyl groups that can be permanent or temporary. This information will help us graft drug-like properties into RNA by judicious installation of specific alkyl groups. For RNA therapies to be successful they need to stay out of the liver and reach their targets. In another major objective we will use a reaction developed in my group to functionalize the surface of exosome nanoparticles isolated from cells and use these as vehicles to deliver our synthetic RNAs. Boron assisted ligation reactions for chemical biology Research Project | 1 Project MembersDespite great advances over the past decade, the field of bioconjugation remains deficient in some key areas. For example, reactions with high rate constants in biological media are important but rare. Since the rate of chemical coupling reactions decrease quadratically with concentration, high-rate constant reactions are essential to monitor biological processes at relevant concentrations. My group has developed a series of high-rate constant coupling reactions and in the present proposal we outline how these reactions could be exploited in chemical biology. 12 12 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 13 foundShow per page10 10 20 50 Transfidelity Research Project | 1 Project MembersImported from Grants Tool 4718138 Exploring DNA encoded library technology against cell surface targets Research Project | 1 Project MembersImported from Grants Tool 4708804 A novel DNA encoded library selection method for identifying binders and their affinity to targets Research Project | 1 Project MembersImported from Grants Tool 4699612 Novel Payloads for Antibody Drug Conjugates used for Cancer Therapies Research Project | 1 Project MembersImported from Grants Tool 4699776 Amplifying information on binding and function from DNA encoded collections of small molecules Research Project | 1 Project MembersNo Description available ExploDProteins Research Project | 1 Project MembersHere I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translational possibilities in cancer. Cancer cells are often acutely sensitive to DNA damage because they have one or more faulty DNA damage response pathways - a feature that makes them highly dependent on their remaining DNA repair systems. We will pioneer two novel and related chemical approaches for selectively degrading proteins by modulating DNA damage response pathways with bifunctional DNA damaging molecules. We will do this by reprogramming E3 ligases. E3 ligases are multi-protein complexes that catalyse the formation of polyubiquitin chains on its substrates, leading to their degradation in the protein recycling station known as the proteasome. A recent revolutionary advance in chemical biology is to use small molecules to change the specificity of E3 ligases, leading to the degradation of user-defined proteins. By degrading proteins instead of inhibiting them, these small molecules achieve levels of functional modulation typically only possible with genetic techniques. We are inspired by this new protein degradation technology, but will take it in a new direction. Chemical damage of DNA recruits E3 ligases as well as critical DNA damage response proteins in preparation for DNA repair. We will invent a new generation of small molecule protein degradation catalysts and reagents by repurposing these natural responses to DNA damage. We will accomplish our goal with three aims: Aim 1: Use DNA damage as a homing signal for induced protein degradation Aim 2: Use direct repair of DNA damage by the repair protein methylguanine methyltransferase (MGMT) to promote the degradation of other proteins Aim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damage I propose an ambitious project that will create conceptually novel ways to study the DNA damage response and potentially build new medicines. Targeting DNA Replication Stress through Novel Small-Molecule Degraders in Cancer Research Project | 3 Project MembersNo Description available Formyl- and acylborylation of alkynes to unlock the potential of boron heterocycles in drug discovery Research Project | 1 Project MembersNo Description available Chemical Tailoring of RNAs and Vesicles to Create New Drugs Research Project | 1 Project MembersRNA therapeutics suffer from stability, immunogenicity, and delivery problems. We will take inspiration from two recent discoveries in biology to help us build better RNA therapeutics: 1. Methylated RNAs are substrates for direct reversal repair enzymes and their methylation state controls their function; 2. Exosomes are natural delivery systems for RNAs of all sizes. The fact that Nature uses alkyl groups to control the function of RNAs suggests that chemists could too. I will study which alkyl groups on RNA get repaired, and which do not, facilitating the design of RNAs with alkyl groups that can be permanent or temporary. This information will help us graft drug-like properties into RNA by judicious installation of specific alkyl groups. For RNA therapies to be successful they need to stay out of the liver and reach their targets. In another major objective we will use a reaction developed in my group to functionalize the surface of exosome nanoparticles isolated from cells and use these as vehicles to deliver our synthetic RNAs. Boron assisted ligation reactions for chemical biology Research Project | 1 Project MembersDespite great advances over the past decade, the field of bioconjugation remains deficient in some key areas. For example, reactions with high rate constants in biological media are important but rare. Since the rate of chemical coupling reactions decrease quadratically with concentration, high-rate constant reactions are essential to monitor biological processes at relevant concentrations. My group has developed a series of high-rate constant coupling reactions and in the present proposal we outline how these reactions could be exploited in chemical biology. 12 12
Exploring DNA encoded library technology against cell surface targets Research Project | 1 Project MembersImported from Grants Tool 4708804
A novel DNA encoded library selection method for identifying binders and their affinity to targets Research Project | 1 Project MembersImported from Grants Tool 4699612
Novel Payloads for Antibody Drug Conjugates used for Cancer Therapies Research Project | 1 Project MembersImported from Grants Tool 4699776
Amplifying information on binding and function from DNA encoded collections of small molecules Research Project | 1 Project MembersNo Description available
ExploDProteins Research Project | 1 Project MembersHere I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translational possibilities in cancer. Cancer cells are often acutely sensitive to DNA damage because they have one or more faulty DNA damage response pathways - a feature that makes them highly dependent on their remaining DNA repair systems. We will pioneer two novel and related chemical approaches for selectively degrading proteins by modulating DNA damage response pathways with bifunctional DNA damaging molecules. We will do this by reprogramming E3 ligases. E3 ligases are multi-protein complexes that catalyse the formation of polyubiquitin chains on its substrates, leading to their degradation in the protein recycling station known as the proteasome. A recent revolutionary advance in chemical biology is to use small molecules to change the specificity of E3 ligases, leading to the degradation of user-defined proteins. By degrading proteins instead of inhibiting them, these small molecules achieve levels of functional modulation typically only possible with genetic techniques. We are inspired by this new protein degradation technology, but will take it in a new direction. Chemical damage of DNA recruits E3 ligases as well as critical DNA damage response proteins in preparation for DNA repair. We will invent a new generation of small molecule protein degradation catalysts and reagents by repurposing these natural responses to DNA damage. We will accomplish our goal with three aims: Aim 1: Use DNA damage as a homing signal for induced protein degradation Aim 2: Use direct repair of DNA damage by the repair protein methylguanine methyltransferase (MGMT) to promote the degradation of other proteins Aim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damage I propose an ambitious project that will create conceptually novel ways to study the DNA damage response and potentially build new medicines.
Targeting DNA Replication Stress through Novel Small-Molecule Degraders in Cancer Research Project | 3 Project MembersNo Description available
Formyl- and acylborylation of alkynes to unlock the potential of boron heterocycles in drug discovery Research Project | 1 Project MembersNo Description available
Chemical Tailoring of RNAs and Vesicles to Create New Drugs Research Project | 1 Project MembersRNA therapeutics suffer from stability, immunogenicity, and delivery problems. We will take inspiration from two recent discoveries in biology to help us build better RNA therapeutics: 1. Methylated RNAs are substrates for direct reversal repair enzymes and their methylation state controls their function; 2. Exosomes are natural delivery systems for RNAs of all sizes. The fact that Nature uses alkyl groups to control the function of RNAs suggests that chemists could too. I will study which alkyl groups on RNA get repaired, and which do not, facilitating the design of RNAs with alkyl groups that can be permanent or temporary. This information will help us graft drug-like properties into RNA by judicious installation of specific alkyl groups. For RNA therapies to be successful they need to stay out of the liver and reach their targets. In another major objective we will use a reaction developed in my group to functionalize the surface of exosome nanoparticles isolated from cells and use these as vehicles to deliver our synthetic RNAs.
Boron assisted ligation reactions for chemical biology Research Project | 1 Project MembersDespite great advances over the past decade, the field of bioconjugation remains deficient in some key areas. For example, reactions with high rate constants in biological media are important but rare. Since the rate of chemical coupling reactions decrease quadratically with concentration, high-rate constant reactions are essential to monitor biological processes at relevant concentrations. My group has developed a series of high-rate constant coupling reactions and in the present proposal we outline how these reactions could be exploited in chemical biology.
