A5017997902- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Chromatin Remodeling and Cancer
- Multiple Myeloma Research and Treatments
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Steroid Chemistry and Biochemistry
- Cholesterol and Lipid Metabolism
- Histone Deacetylase Inhibitors Research
- PI3K/AKT/mTOR signaling in cancer
- Hydrogen embrittlement and corrosion behaviors in metals
- Receptor Mechanisms and Signaling
- HIV Research and Treatment
- Software Testing and Debugging Techniques
- Chemical Reaction Mechanisms
- HIV/AIDS drug development and treatment
- Hormonal Regulation and Hypertension
- Sphingolipid Metabolism and Signaling
- Cholinesterase and Neurodegenerative Diseases
- Signaling Pathways in Disease
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and Reactions of Organic Compounds
University of Dundee
2018-2025
Takeda (Japan)
2020-2021
Takeda (United Kingdom)
2017-2018
Vitenparken
2017
Milton District Hospital
2017
Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation method directly determine binding parameters for complex kinetics has been reported, and it remains be addressed whether tuning PROTAC complexes may effective strategy improve efficiency targeted protein degradation. Here, we develop...
Abstract Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target E3 ligase, resulting in ubiquitylation proteosome-dependent target. In clinic, oral route administration is option choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally...
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule potently degrades 13 out 17 most alleles. Compared inhibition, degradation...
Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using simple mathematical modeling degradation, we find that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis, such GSPT1...
Abstract Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24 S -hydroxycholesterol, the primary mechanism of catabolism in brain. The therapeutic potential CH24H activation has been extensively investigated, whereas effects inhibition remain poorly characterized. In this study, was investigated using newly identified small molecule, soticlestat (TAK-935/OV935). biodistribution and target engagement assessed mice. CH24H-knockout mice showed...
Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays role in the homeostasis of brain cholesterol by converting to 24S-hydroxycholesterol (24HC). Despite wide range potential CH24H as drug target, no potent and selective inhibitors have been identified. Here, we report on structure-based design (SBDD) novel 4-arylpyridine derivatives based X-ray co-crystal structure hit derivative 1b. Optimization led us identify 3v...
Summary Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using mathematical modelling degradation, we demonstrate that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis,...
The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide recruited by most targeted protein degraders (PROTACs molecular glues) in clinical development. Biophysical structural investigation CRBN has been limited current constructs that either require co-expression with adaptor DDB1 or inadequately represent full-length protein, high-resolution structures degrader ternary complexes remaining rare. We present design
Despite the high prevalence of cancers driven by KRAS mutations, to date only G12C mutation has been clinically proven be druggable via covalent targeting mutated cysteine amino acid residue (1). However, in many cancer indications other such as G12D and -V, are far more prevalent small molecule concepts that can address a wider variety oncogenic alleles clinical demand (2). Here we show single used simultaneously potently degrade 13 out 17 most alleles, including those not yet tractable...
Copper catalyzed aldehyde–alkyne–amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, selection linkers was purified by chiral HPLC afford single enantiomers, the absolute configuration which determined vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting...
Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative diseases. These molecules have non-occupancy based, sub-stoichiometric mechanism of action which results in removal target proteins from cells, presenting opportunities interrogate intervene pathogenic signalling. Identifying chemical starting points for PROTACs remains largely empirical process...
Abstract The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide recruited by most targeted protein degraders (PROTACs molecular glues) in clinical development. Biophysical structural investigation CRBN has been limited current constructs that either require co-expression with adaptor DDB1 or inadequately represent full-length protein, high-resolution structures ternary complexes remaining rare. We present design midi , a construct readily...
Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit target E3 ligase, resulting in ubiquitylation proteosome-dependent target. The oral route administration is option choice clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally bioavailable...
A modular synthetic approach was developed that yielded thirty diverse lead-like scaffolds suitable for CNS drug discovery.
ABSTRACT Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation method directly determine binding parameters for complex kinetics has been reported, and it remains be addressed whether tuning PROTAC complexes may effective strategy improve efficiency targeted protein degradation. Here, we...
Targeted protein degradation of a interest (POI) by Proteolysis Targeting Chimeras (PROTACs) is an attractive approach for dealing with formerly undruggable targets. PROTACs are heterobifunctional molecules that connect POI-binding and E3-ligase (E3) binding motif linker. The simultaneous formation ternary POI::PROTAC::E3 complex (TC) induces proximity between the POI E3, allowing POI-ubiquitination subsequent induction proteasomal degradation. Despite availability many three-dimensional...