Discovery of new lead structures for development of AMPK modulators

Jan  Lanz

Discovery of new lead structures for development of AMPK modulators

Jan Lanz

Institut for Fysik, Kemi og Farmaci

Publikation: Afhandling › Ph.d.-afhandling

Abstract

AMP-aktiveret proteinkinase AMPK fungerer som en hovedregulator for opretholdelsen af energihomeostasen i celler og i hele organismen. Anormale aktivitetsprofiler for AMPK forårsager patologiske lidelser, og en stigende mængde data validerer AMPK som et farmakologisk mål i behandlingen af menneskelige sygdomme, for eksempel metaboliske lidelser, kræft og neurodegenerative sygdomme. Forbindelsen mellem AMPK-isoformerne og de normale såvel som patologiske processer er endnu uklar. Derfor er der behov for yderligere undersøgelser og nye værktøjer til at studere AMPK’s fysiologiske funktioner. Fokus var oprindeligt på udvikling af allosteriske AMPK-aktivatorer. Imidlertid er der kun offentliggjort nogle få studier, der beskriver opdagelsen af inhibitorer. Derfor er litteraturoverblikket i Manuscript I tiltænkt som en inspirationskilde for de videnskabelige kredse til at udvikle nye AMPK-inhibitorer.

Under mit ophold på GIDD, Griffith Universitet, Brisbane, Australien i prof. Ronald J. Quinns gruppe blev der foretaget en screeningskampagne, som havde til formål at opdage nye AMPK-modulatorer. Kapitel 2 beskriver det udførte arbejdet samt de screenede forbindelsesbiblioteker og fremhæver nogle eksempler på nye AMPK-modulatorer. En af forbindelserne blev valgt til den efterfølgende optimering.

Kapitel 3 beskriver den medicinalkemiske optimering af det valgte ‘hit’. De opdagede pyrrolo[2,3-c]pyridiner blev gennem en iterativ proces med in silico-understøttet ligandbaseret design, organisk syntetisk kemi og biologisk testning til de nye pyrrolo[2,3-c]pyridin- og thieno[2,3-c]pyridinbaserede AMPK-inhibitorserier. Glædeligvis viser ‘lead’-strukturen TUG-1874 (3.88) en fremragende selektivitetsprofil under inhiberingen af alle screenede AMPK-isoformer, og det blev yderligere vist, at TUG-1874 inhiberer AMPK i celler. Desuden er TUG-1874’s potens og mål-selektivitetsprofil bedre end den almindeligt anvendte AMPK-inhibitor Compound C.

Slutteligt beskriver kapitel 4 den regioselektive N-methylering af pyrrolo[2,3-c]pyridiner og diskuterer, hvordan udvalgte forbindelsers fluorescerende egenskaber potentielt kan anvendes i fluorescerende værktøjsforbindelser.

Originalsprog	Engelsk
Bevilgende institution	Syddansk Universitet
Vejledere/rådgivere	Ulven, Trond, Hovedvejleder Quinn, Ronald J., Bivejleder, Ekstern person
Dato for forsvar	21. dec. 2017
Udgivelsessted	Odense
Udgiver	Syddansk Universitet. Det Naturvidenskabelige Fakultet
Status	Udgivet - 2018

Note vedr. afhandling

Afhandlingen kan læses på SDUs bibliotek.

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Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

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abstract = "AMP-activated protein kinase AMPK functions as a master switch to maintain cellular and whole-body energy homeostasis. Abnormal activity profiles of AMPK cause pathological disorders, and growing evidence supports pharmacological targeting of AMPK as a promising approach to treat human diseases such as metabolic disorders, cancer and neurodegenerative diseases. However, isoform-dependent signaling of AMPK in health and disease remains largely elusive. Therefore, continuous investigations are required as well as new tools to study the physiological functions of AMPK. Previously, the focus has been directed towards development of allosteric AMPK activators whereas only few attempts have been reported describing AMPK inhibitors. Thus, the literature review summarized in Manuscript I may provide stimulating starting points to the scientific community to promote AMPK inhibitor development. To provide novel small-molecule AMPK modulators, a screening campaign was conducted during my environmental exchange at GRIDD, Griffith University, Brisbane, Australia in the group of Prof. Ronald J. Quinn. Chapter 2 discusses the screened compound libraries and highlights selected discoveries of new AMPK modulators, including the hit scaffold which was selected for subsequent optimization. Chapter 3 outlines the optimization of the promising screening hit scaffold via state-of-the-art medicinal chemistry. The discovered pyrrolo[2,3-c]pyridines were altered in an iterative process, including in silico-supported ligand-based design, organic synthetic chemistry, and biological testing, to provide the novel pyrrolo[2,3-c]pyridine- and thieno[2,3-c]pyridine-based AMPK inhibitor series. To our delight, the lead structure TUG-1874 (3.88) displays an excellent kinase-selectivity profile while inhibiting activity of all screened AMPK complexes, and was further shown to inhibit AMPK in cells. Moreover, potency and target-selectivity profile of TUG-1874 are superior compared to the commonly used AMPK inhibitor Compound C. Lastly, Chapter 4 describes the regioselective N-alkylation of pyrrolo[2,3-c]pyridine intermediates and discusses fluorescent properties of selected compounds in the context of a prospective use in fluorescent tool compounds.",

author = "Jan Lanz",

year = "2018",

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publisher = "Syddansk Universitet. Det Naturvidenskabelige Fakultet",

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AB - AMP-activated protein kinase AMPK functions as a master switch to maintain cellular and whole-body energy homeostasis. Abnormal activity profiles of AMPK cause pathological disorders, and growing evidence supports pharmacological targeting of AMPK as a promising approach to treat human diseases such as metabolic disorders, cancer and neurodegenerative diseases. However, isoform-dependent signaling of AMPK in health and disease remains largely elusive. Therefore, continuous investigations are required as well as new tools to study the physiological functions of AMPK. Previously, the focus has been directed towards development of allosteric AMPK activators whereas only few attempts have been reported describing AMPK inhibitors. Thus, the literature review summarized in Manuscript I may provide stimulating starting points to the scientific community to promote AMPK inhibitor development. To provide novel small-molecule AMPK modulators, a screening campaign was conducted during my environmental exchange at GRIDD, Griffith University, Brisbane, Australia in the group of Prof. Ronald J. Quinn. Chapter 2 discusses the screened compound libraries and highlights selected discoveries of new AMPK modulators, including the hit scaffold which was selected for subsequent optimization. Chapter 3 outlines the optimization of the promising screening hit scaffold via state-of-the-art medicinal chemistry. The discovered pyrrolo[2,3-c]pyridines were altered in an iterative process, including in silico-supported ligand-based design, organic synthetic chemistry, and biological testing, to provide the novel pyrrolo[2,3-c]pyridine- and thieno[2,3-c]pyridine-based AMPK inhibitor series. To our delight, the lead structure TUG-1874 (3.88) displays an excellent kinase-selectivity profile while inhibiting activity of all screened AMPK complexes, and was further shown to inhibit AMPK in cells. Moreover, potency and target-selectivity profile of TUG-1874 are superior compared to the commonly used AMPK inhibitor Compound C. Lastly, Chapter 4 describes the regioselective N-alkylation of pyrrolo[2,3-c]pyridine intermediates and discusses fluorescent properties of selected compounds in the context of a prospective use in fluorescent tool compounds.

M3 - Ph.D. thesis

PB - Syddansk Universitet. Det Naturvidenskabelige Fakultet

CY - Odense

ER -

Discovery of new lead structures for development of AMPK modulators

Abstract

Note vedr. afhandling

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