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Yousef Najajreh, Associate Professor

Yousef Najajreh, Associate Professor
Department: Anticancer Drugs Research Lab
Faculty: Faculty of Pharmacy
Specialization: Medicinal Chemistry and Drug Discovery
Host French partner: Sorbonne Université, Cassan A 6e étage BC 256,UMR 8256 - ERL INSERM U1164
Faculté des Sciences et Ingénierie 7 quai Saint-Bernard | 75005 Paris
Host Department: Institut of Biology Paris Seine, UMR 8256 Biological Adaptation and Aging
French Partner: Chahrazade EL AMRI, Professor (Full)
Research Domain: Leader of the Molecular and Functional Enzymology Group Integrative Cellular Ageing and Inflammation (ICAI), Biochemistry and Molecular Biology.
Research Project Title: Design, synthesis and biological evaluation of low-molecular weight inhibitors of immunoproteasome for treatment of cancer
Research Project Purpose: Emerging resistance and the reported toxicities of currently applied chemotherapeutics makes the need for novel therapeutic approaches. The proteasome is a multicatalytic enzyme essential to maintain cell protein homeostasis. It has been validated as a target for fighting cancer with three covalent drugs used for the treatment of liquid cancers. Nevertheless, side-effects and resistance were observed during treatment. Today, the inducible immunoproteasome appears as a better target than constitutive proteasome in order to lower side-effects. In this project, we propose to develop inhibitors acting selectively on immunoproteasome. Conversely to the present drugs, the new inhibitors are devoid of a reactive functional group and as such are classified as non-covalent inhibitors that act based on target affinity. The design of the novel inhibitors will be based on known high resolution crystal structures of immuno- and constitutive proteasomes. The synthesis of the designed inhibitors will be done at Al-Quds University. Their biological in vitro and in cellulo evaluation will be performed at Sorbonne University. Prof. EL AMRI team has a wide experience in the development of proteasome inhibitors (25 publications, 5 patents). Prof. Najajreh team at AQU masters the chemistry of low molecular-weight entities.
Main outputs/results:
- Rational design of immunoproteasome inhibitors
- This project will lead to the identification and discovery of novel immunoproteasome inhibitor. Newly identified compounds will be synthesized, purified and characterized.
- Assessment of Biological Activity: Afterwards the compounds will be tested for their effects on cells derived of human cancers.
- Optimizing the druglikeness: potent inhibitor will be treated as “hits” that will subjected to further optimizations with the goal to end up with “leads” for further drug development processes.
- Publications as well as potentially “patentable” knowledge are expected outcomes of this research.
Expected future impact:
- Upon successful completion this collaborative effort novel series of immunoproteasome inhibitors will be identified.
- A Palestinian master student will be trained at to use cellular and biomolecular techniques Prof. EL AMRI
- Accomplishment of Master Thesis for a Palestinian student in a advanced research topic and well-equipped labs.
Future Plan:
- Implementing the action plan depicted in the body of the application.
- Proceeding with preparing additional compounds (designed Library-1) at Prof Najajreh lab.
- Delivering the first group of compounds to Prof. EL AMRI lab.
- Assessing the biological activity of the novel compounds against cancer cells.
- Explore the mechanism of action, selectivity and druglikeness of the identified inhibitors.
Main Impact: serving cancer patients by discovery of novel small molecular agents that exert selective and improved action against cancer cells.