KLKs4OvCa · Targeting human kallikreins involved in ovarian cancer pathogenesis: novel activity based probes and kallikrein-based therapeutic strategies.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-10-04 → 2024-01-12
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Targeting human kallikreins involved in ovarian cancer pathogenesis: novel activity based probes and kallikrein-based therapeutic strategies.
Aberrant protein ubiquitination and degradation are linked to the pathogenesis of several diseases including cancer, neurodegeneration, and metabolic diseases, that would benefit from targeted protein stabilization (TPS). Heterobifunctional molecules able to induce targeted protein deubiquitination (deubiquitinase targeting chimeras, DUBTACs) via engagement of a deubiquitinase (DUB) to a protein of interest (POI), can be recruited to stabilize proteins and restore their function (see figure). The identification of suitable DUB ligands has proven challenging and remain to be thoroughly explored. To overcome this limitation, we aimed to use covalent ligand discovery to explore novel DUBs for targeted protein stabilization. We established the following objectives: 1. WP1 (Objective 1): Development of a high-throughput screening platform for the discovery of covalent ligands for different effector proteins, using Ubiquitin C terminal hydrolase L1 (UCHL1) as model effector protein. 2. WP2 (Objective 2): Identification and development of selective ligands for UCHL1 targeting non catalytic cysteines through covalent fragment screening. 3. WP3 (Objective 3): Synthesis of UCHL1 DUBTACs and elucidation of mechanism of action (MoA) on protein stabilisation and ubiquitin biology.
Data: CORDIS, © European Union
Project objective
Ovarian cancer (OvCa) is one of the most fatal female gynaecological malignancies, resulting in 180,000 deaths annually. The majority of patients have metastatic disease at time of diagnosis, thus, early diagnosis of OvCa remains a challenge to our society. In addition, the low survival rates over the past decades have remained largely unchanged, evidencing the need of new therapies for OvCa. Kallikrein-related peptidases (KLKs) are a family of 14 serine proteases which form a cross activation network known as the KLK activome. KLKs show diverse tissue expression and physiological function, and aberrant KLK expression and activity has been related to several pathological conditions including skin diseases, neurodegenerative disorders and cancer. In OvCa, KLKs4,5,6 & 7 levels are upregulated and associated with its unfavourable prognosis, therefore, KLKs4,5,6 & 7 are considered potential drug targets and biomarkers for OvCa. However, KLK activity is decoupled from simple abundance, and the contribution of each KLK activity in OvCa progression remain poorly understood. In this project, I will develop selective (quenched)-Activity Based Probes ((q)-ABPs) for KLKs4,5,6 & 7 and quantify the active enzyme fraction of each KLK to determine their contribution to OvCa. Additionally, I will develop proteolysis targeting chimeras (PROTACs) which can be selectively activated by specific KLKs to unlock their potential as therapeutic targets for OvCa. This proposal aims to deliver a versatile platform to interrogate the application of KLKs4,5,6 & 7 as biomarkers and therapeutic targets for OvCa, with potential application to other KLK- and serine protease-related disorders. My participation in this proposal will allow to bring key knowledge to face the challenging objectives and receive high-quality training that will provide me with a solid and diversified groundwork to become and independent researcher in the drug discovery field.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union