Design and Synthesis of Novel Kinase Inhibitors for the Treatment of Chronic Respiratory Diseases

Mazzucato, Roberta (2021) Design and Synthesis of Novel Kinase Inhibitors for the Treatment of Chronic Respiratory Diseases, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biotecnologiche, biocomputazionali, farmaceutiche e farmacologiche, 33 Ciclo. DOI 10.48676/unibo/amsdottorato/9617.
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In 2017, Chronic Respiratory Diseases accounted for almost four million deaths worldwide. Unfortunately, current treatments are not definitive for such diseases. This unmet medical need forces the scientific community to increase efforts in the identification of new therapeutic solutions. PI3K delta plays a key role in mechanisms that promote airway chronic inflammation underlying Asthma and COPD. The first part of this project was dedicated to the identification of novel PI3K delta inhibitors. A first SAR expansion of a Hit, previously identified by a HTS campaign, was carried out. A library of 43 analogues was synthesised taking advantage of an efficient synthetic approach. This allowed the identification of an improved Hit of nanomolar enzymatic potency and moderate selectivity for PI3K delta over other PI3K isoforms. However, this compound exhibited low potency in cell-based assays. Low cellular potency was related to sub optimal phys-chem and ADME properties. The analysis of the X-ray crystal structure of this compound in human PI3K delta guided a second tailored SAR expansion that led to improved cellular potency and solubility. The second part of the thesis was focused on the rational design and synthesis of new macrocyclic Rho-associated protein kinases (ROCKs) inhibitors. Inhibition of these kinases has been associated with vasodilating effects. Therefore, ROCKs could represent attractive targets for the treatment of pulmonary arterial hypertension (PAH). Known ROCK inhibitors suffer from low selectivity across the kinome. The design of macrocyclic inhibitors was considered a promising strategy to obtain improved selectivity. Known inhibitors from literature were evaluated for opportunities of macrocyclization using a knowledge-based approach supported by Computer Aided Drug Design (CADD). The identification of a macrocyclic ROCK inhibitor with enzymatic activity in the low micro molar range against ROCK II represented a promising result that validated this innovative approach in the design of new ROCKs inhibitors.

Tipologia del documento
Tesi di dottorato
Mazzucato, Roberta
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Chronic Respiratory Diseases, COPD, Asthma, Kinases, Lipid kinases, PI3K, PI3k delta,PI3K inhibitors, inflammation, PAH, ROCKs, ROCK I/II, ROCK inhibitors, vasodilating effect, Ser/Thr Kinases
Data di discussione
22 Marzo 2021

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