Periodic Reporting for period 1 - BRAINHIB (Integrated drug discovery approach to generate brain-penetrant inhibitors of glioblastoma cell proliferation)
Berichtszeitraum: 2018-03-01 bis 2020-02-29
The first specific objective of the project was the design and synthesis and novel small molecule kinase inhibitors. To achieve this objective three different scaffolds were used as templates to design three different libraries upon modification of the key positions. Focus was given to the achievement of the physicochemical properties which allow a blood brain barrier penetration, such as pKa, PSA, ClogD, CLogP, HBD and molecular weight. A total of 99 novel compounds divided in 2 libraries, were synthesised.
The second specific objective was the phenotypic screening of compound libraries. To achieve this objective our approach was three fold: A first screening in two commercial glioma cell lines, a second screening in blood brain barrier simplified models and a third screening in patient-derived glioblastoma cells. Results of the first and second screening were used to inform further synthesis, while screening on patient-derived glioma spheroids was used as the validation of hits. Additionally, to newly synthesised compounds, two previously synthesised libraries were tested. A total of 199 final compounds were tested. The results of these screening campaigns informed further synthesis in an iterative manner. Potent hits with submicromolar potency against glioma cells were identified.
The third specific objective was the target deconvolution studies of most potent hits. For this specific objective we took advantage of clear relationships found on kinase profiling studies with a critical tumour driving pathway, to develop structure activity relationships. This research has been recently published as an open access article in Bioorganic and Medicinal Chemistry (Valero T, et al. Bioorg Med Chem 2020 1;28(1):115215). Preliminary results were and are being disseminated across scientific conferences, network groups and collaborators. Further original structures will be assessed for patentability before any kind of disclosure.