Proteolysis targeting chimeras of Anaplastic lymphoma kinase

Diplôme Master Proteolysis targeting chimeras of Anaplastic lymphoma kinase eng 2020-12-08 author Werlen Sarah Virginie 856749 director Scapozza Leonardo 600318 Anaplastic lymphoma kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL) is a disease most commonly found in children and young adults (median age 34) with a slight male dominance. This cancer infects mainly lymph nodes, nevertheless it can be involved in other site than the lymph like the skin, soft tissues and bones. ALK+ ALCL constantly displays ALK gene rearrangements but in the majority of cases, up to 80%, ALCLs harbour the t(2;5)(p23;q35) translocation. This translocation results in the fusion of the nucleolar phosphoprotein gene nucleophosmin 1 (NPM1) with the anaplastic lymphoma kinase (ALK) gene. The resultant protein is constitutively activated and results in aberrant down-stream signalling, which leads to the oncogenic developments of cells. Treatments to cure the disease have already been developed such as tyrosine kinase inhibitor (e.g. Crizotinib, Ceretinib), chemotherapy and autologous stem cell transplantation or anti-CD30 (Brentuximab Vedotin). However, those therapies are confronted with resistance, thence the expansion of the range of treatment, with novel medication, would allow the overachieving of the resistance. Proteolysis Targeting Chimera (PROTAC) could be an answer to that problematic. It is an emerging therapeutic tool inducing the degradation of the defected protein by triggering the proteasome. The aim of this work is to synthesis two types of compound: a possibly effective PROTAC targeting NPM-ALK fusion protein and a possibly efficient NPM-ALK inhibitor. PROTAC is a compound divisible in three parts: a ligand for binding to the targeted protein, a linker and a ligand for recruiting E3 ligase. Based on the biological results acquired by PhD. S. Pannilunghi (School of Pharmacy, University of Geneva) in collaboration with Dr. L. Mologni (School of Medicine and Surgery, UNIMIB, Milano-Bicocca), the ligand binding to NPM-ALK is a functionalized pyrido[2,3b]indole core (alpha-carboline). The first part of the project was dedicated to the synthesis of the alpha-carboline core derivates: depending on the halogenation either on the C-3 or C-4 position. The chlorine linked on the C-3 or C-4 carbon supplies a key partner to the Suzuki-Miyaura coupling in order to form a C(sp2)-C(sp2) bond. Secondly, the click reaction was executed on the C-3 series, getting a reaction between the terminal alkyne, obtained during the first part of this project, and a “E3 ligase binder-PEG4” azide compound, already available in the laboratory. The resulting product was lastly deprotected to produce the final PROTAC. About the C-4 series, the aim of this work was to produce a C-4 substituted analogue to test as a simple NPM-ALK inhibitor before making a potential PROTAC out of it. Dewey 615 Master en Pharmacie 31 Section des sciences pharmaceutiques 17 false 880 Biochimie pharmaceutique 3c9b5f34-e844-46da-a416-bf8dbc314b18 Master thesis Restricted 201209092307_werlens0__TPR.pdf 2583015 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Werlen, Sarah Virginie