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Étude De L'action Du PBRM, Un Inhibiteur De La 17B

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Étude De L'action Du PBRM, Un Inhibiteur De La 17B Étude de l’action du PBRM, un inhibiteur de la 17β-hydroxystéroïde déshydrogénase (17β-HSD) type 1 …Qui mena à la découverte fortuite d’un 1er activateur de la 17β-HSD type 12 Mémoire Alexandre Trottier Maîtrise en médecine moléculaire Maître ès sciences (M. Sc.) Québec, Canada © Alexandre Trottier, 2014 Résumé Les 17β-hydroxystéroïdes déshydrogénases (17β-HSD) sont un groupe de 15 enzymes connues avant tout pour leur rôle dans le métabolisme des hormones sexuelles. La 17β-HSD1 est responsable de la toute dernière étape dans la fabrication des estrogènes actifs. Cela en fait une cible intéressante pour traiter l’endométriose et le cancer du sein qui sont stimulées par ces hormones. Le dérivé stéroïdien PBRM, conçu dans notre laboratoire, est l’une des rares molécules ayant démontré une inhibition forte et spécifique de la 17β-HSD1. Lors des présents travaux, l’effet de l’inhibiteur s’est avéré irréversible, sélectif et durable tout en présentant un profil intéressant chez la souris. Durant ce processus, plusieurs composés n’ayant pas les qualités requises ont été mis de côté. Parmi eux, l’un s’est avéré être un activateur de la 17β-HSD12, une enzyme essentielle dans l’élongation des acides gras. Il s’agit là du premier activateur rapporté pour la famille des 17β-HSD. III Abstract 17β-Hydroxysteroid dehydrogenases (17β-HSD) are a group of 15 enzymes known firstly for their involvement in sexual hornomes metabolism. 17β-HSD1 is responsible of the last step in the biosynthesis of potent estrogens. It is thus an interesting target to treat diseases stimulated by those hormones such as endometriosis and breast cancer. PBRM, a steroidal inhibitor developed in our laboratory, is one of the few molecules that shown a strong and specific inhibition of 17β-HSD1. The present works showed that the inhibitory effect is irreversible, selective and long-lasting while showing an interesting profil in mice. During that process, many other compounds were tested but didn’t have the required qualities. Among them, one seemed to stimulate the activity of 17β-HSD12, an essential enzyme for fatty acids elongation also involved in estrogen metabolism. It is the first reported activator for a member of 17β-HSD family. V Table des matières Résumé .............................................................................................................................................................. III Abstract ............................................................................................................................................................... V Table des matières ............................................................................................................................................ VII Liste des tableaux .............................................................................................................................................. IX Liste des schémas ............................................................................................................................................. XI Liste des figures ............................................................................................................................................... XIII Liste des abréviations et symboles ................................................................................................................ XVII Épigraphe ...................................................................................................................................................... XXIII Remerciements .............................................................................................................................................. XXV Avant-propos ................................................................................................................................................ XXVII Introduction ......................................................................................................................................................... 1 1. Les estrogènes ........................................................................................................................................... 1 1.1 Définition ............................................................................................................................................ 1 1.2 Récepteurs estrogéniques ................................................................................................................. 2 1.2.1 Récepteur des estrogènes α (ERα) .............................................................................................. 3 1.2.2 Récepteur des estrogènes β (ERβ) .............................................................................................. 4 1.2.3 Récepteur estrogénique couplé aux protéines G (GPER) ............................................................. 4 1.2.4 Autres ............................................................................................................................................ 5 1.3 Note ................................................................................................................................................... 5 1.4 Rôles physiologiques des estrogènes ............................................................................................... 5 1.4.1 Reproduction ................................................................................................................................. 6 1.4.2 Squelette et muscles ..................................................................................................................... 8 1.4.3 Système digestif et métabolisme ................................................................................................... 8 1.4.4 Neurologique ................................................................................................................................. 9 1.4.5 Autres .......................................................................................................................................... 10 2. Maladies sensibles aux estrogènes .......................................................................................................... 10 2.1 Cancers ........................................................................................................................................... 10 2.1.1 Cancer du sein ............................................................................................................................ 11 2.1.2 Cancers du système reproducteur .............................................................................................. 12 2.1.3 Autres cancers ............................................................................................................................ 13 2.2 Endométriose ................................................................................................................................... 13 VII 2.3 Autres ............................................................................................................................................... 14 3. Modulation de la stéroïdogenèse comme approche thérapeutique .......................................................... 14 3.1 Stéroïdogenèse ................................................................................................................................ 15 3.2 Inhiber la biosynthèse des hormones sexuelles .............................................................................. 16 3.2.1 Agoniste/Antagoniste GnRH ........................................................................................................ 16 3.2.2 17α-Hydroxylase/17,20 lyase (CYP17A1) ................................................................................... 16 3.2.3 Aromatase ................................................................................................................................... 18 3.2.4 Stéroïde sulfatase ........................................................................................................................ 19 3.2.5 17β-Hydroxystéroïde déshydrogénase ........................................................................................ 21 3.3 Inhibiteur de la 17β-HSD1 ................................................................................................................ 23 3.3.1 Intérêt thérapeutique.................................................................................................................... 23 3.3.2 Avancées actuelles ...................................................................................................................... 24 4. Activateurs enzymatiques ......................................................................................................................... 25 4.1 Définition et mécanismes ................................................................................................................. 25 4.2 La 17β-HSD12 ................................................................................................................................. 26 5. Objectifs et aperçu des travaux ................................................................................................................ 27 Chapitre 1 .......................................................................................................................................................... 29 Résumé ........................................................................................................................................................
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