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:

1. Rational design of immunoproteasome inhibitors
2. This project will lead to the identification and discovery of novel immunoproteasome inhibitor. Newly identified compounds will be synthesized, purified and characterized. 
3. Assessment of Biological Activity: Afterwards the compounds will be tested for their effects on cells derived of human cancers. 
4. 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. 
5. Publications as well as potentially “patentable” knowledge are expected outcomes of this research.

Expected future impact: 

1. Upon successful completion this collaborative effort novel series of immunoproteasome inhibitors will be identified.
2. A Palestinian master student will be trained at to use cellular and biomolecular techniques Prof. EL AMRI
3. Accomplishment of Master Thesis for a Palestinian student in a advanced research topic and well-equipped labs.

Future Plan: 

1. Implementing the action plan depicted in the body of the application.
2. Proceeding with preparing additional compounds (designed Library-1) at Prof Najajreh lab.
3. Delivering the first group of compounds to Prof. EL AMRI lab.
4. Assessing the biological activity of the novel compounds against cancer cells.
5. 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.