A5039478872- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Cell death mechanisms and regulation
- Chromatin Remodeling and Cancer
- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Histone Deacetylase Inhibitors Research
- Orthopaedic implants and arthroplasty
- RNA Interference and Gene Delivery
- Cancer therapeutics and mechanisms
- Knee injuries and reconstruction techniques
- Bone fractures and treatments
- Microbial Community Ecology and Physiology
- Virus-based gene therapy research
- vaccines and immunoinformatics approaches
- Software Testing and Debugging Techniques
- HIV Research and Treatment
University of Dundee
2020-2025
University of Stuttgart
2018-2020
University of Zagreb
2019
Royal College of Surgeons in Ireland
2017
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...
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 development of novel drug modalities is necessary to overcome the current critical issues in treatment cancer, namely toxicity, insufficient efficacy, and resistance. Unlike classical small molecule inhibitors that only block a single function or interaction protein involved oncogenic signaling, proteolysis-targeting chimeras (PROTACs) degrade entire protein, thus offering potential paradigm shift. PROTACs are bivalent molecules recruit target proximity an E3 ligase, promoting transfer...
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...
Abstract Second generation TRAIL-based therapeutics, combined with sensitising co-treatments, have recently entered clinical trials. However, reliable response predictors for optimal patient selection are not yet available. Here, we demonstrate that a novel and translationally relevant hexavalent TRAIL receptor agonist, IZI1551, in combination Birinapant, clinically tested IAP antagonist, efficiently induces cell death various melanoma models, responsiveness can be predicted by combining...
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...
Antagonists of inhibitors apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death various solid tumors. The IAP antagonist birinapant is currently being tested phase II clinical trials. We herein aimed investigate the antitumor efficacy dacarbazine vitro, both as a single agent and birinapant, melanoma lines. Covering clinically relevant drug concentration ranges, we conducted total 5,400 measurements panel 12 human...
Abstract Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce ternary complex. To drive ubiquitination degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided intra-complex interactions. We hypothesized these molecular recognition features could be enhanced increasing valency. Here we present trivalent PROTACs...
Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce ternary complex. To drive ubiquitination degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided intra-complex interactions. We hypothesized these molecular recognition features could be enhanced increasing valency. Here we present trivalent PROTACs as...
<p><b>Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce ternary complex. To drive ubiquitination degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided intra-complex interactions. We hypothesized these molecular recognition features could be enhanced increasing valency. Here we present...
Bivalent PROTACs work drive protein degradation by simultaneously binding a target and an E3 ligase forming productive ternary complex. We hypothesized that increasing valency within PROTAC could enhanced degradation. Here, we designed trivalent consisting of bivalent BET inhibitor ligand, tethered via branched linker. identified VHL-based SIM1 as low picomolar degrader, with preference for BRD2. Compared to PROTACs, showed more sustained higher efficacy, which led potent anti-cancer...
AimTo assess whether an adenoviral vector carrying the bone morphogenetic protein genes (Ad.BMP-2) can transduce human muscle tissue and direct it toward osteogenic differentiation within one hour.MethodsThis in vitro study, performed at Department of Molecular Biology, Faculty Science, Zagreb from 2012 to 2017, used samples collected during anterior cruciate ligament reconstructions St Catherine Hospital, Zabok. Samples 28 patients were transduced with firefly luciferase cDNA (Ad.luc) by...
Bivalent PROTACs work drive protein degradation by simultaneously binding a target and an E3 ligase forming productive ternary complex. We hypothesized that increasing valency within PROTAC could enhanced degradation. Here, we designed trivalent consisting of bivalent BET inhibitor ligand, tethered via branched linker. identified VHL-based SIM1 as low picomolar degrader, with preference for BRD2. Compared to PROTACs, showed more sustained higher efficacy, which led potent anti-cancer...