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User Story: Dr Maria J. Macias, IRB Barcelona
Targeting SMAD4, a transcription factor protein mutated in tumours and rare diseases
The opportunity to collaborate with these groups thanks to EU-OPENSCREEN has been key to the progress of the project and also to expand our understanding of complex fields like drug discovery and innovation that are new to us.
Maria Macias
User:
Dr Maria J. Macias, ICREA Research Professor and Group Leader, IRB Barcelona, Spain
EU-OPENSCREEN screening partner site:
Dr Aurora Martinez, University of Bergen, Norway
EU-OPENSCREEN chemistry partner site:
Dr Marc Nazaré, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin, Germany
Identifying new compounds with pharmacological applications is not trivial – it requires time and substantial investment. But if successful, it could mean larger scale manufacturing at lower costs than other treatments on the market, facilitating their use in the public health system. EU-OPENSCREEN user Dr Maria Macias worked with two of our partner sites to identify new compounds to treat diseases often overlooked in the pharmaceutical industry.
Currently, there are several unmet needs for new pharmaceuticals in the healthcare sector. A critical example is the development of effective treatments for patients with rare diseases and cancer patients with resistance to existing drugs. For a variety of reasons, however, pharmaceutical companies tend to invest fewer resources into drug development for such conditions.
Dr Maria J. Macias, IRB Barcelona, Spain, is trying to address this gap in cancer and rare disease therapeutics development. Her research aims to identify molecules that modulate the TGF-β pathway, which is key to many important cellular processes and has also been implicated in rare disease pathology and tumour development. Maria is specifically interested in finding compounds that interact with the transcription factor protein SMAD4, a downstream effector of the TGF-β pathway that is often mutated in these patient populations.
To expand on her work in this area, Maria applied for funding through the EU-OPENSCREEN-DRIVE project (Grant Agreement No. 823893), part of the EU’s Horizon 2020 Research and Innovation programme, to collaborate with EU-OPENSCREEN partner sites offering expertise in a range of advanced techniques in early drug development.
Ultimately, Maria received funding for two consecutive projects. One project, granted under the EU-OPENSCREEN-DRIVE Small Molecule Screening Call 2019, was in collaboration with Dr Aurora Martinez, leader of the Biorecognition Lab at the University of Bergen (UiB), Norway. For this project, the UiB team performed high-throughput screening of over 100,000 diverse compounds based on differential scanning fluorimetry (DSF) to identify SMAD4 interaction partners. This study involved the preparation of recombinant proteins and monitoring of protein–compound interactions with estimation of binding affinity using the DSF thermal shift assay.
Through the EU-OPENSCREEN-DRIVE Medicinal Chemistry Call 2021/2022, Maria was funded for a second project with Dr Marc Nazaré of the Leibniz Research Institute for Molecular Pharmacology (FMP) Berlin, Germany, for the identification of common structural features in the validated hits identified in the screening campaign performed at UiB. Following the identification of the most promising scaffolds, the FMP team carried out a hit expansion in which other chemical entities with similar features were scouted throughout the commercially available libraries, and their activity as SMAD4 ligands was assessed. The knowledge acquired through the hit expansion was then applied in a hit optimisation to design and synthesise new potential SMAD4 ligands.
According to Maria, both projects were highly synergistic, and each team contributed valuable expertise toward the accelerated discovery of promising SMAD4-targeted therapeutics. Key results of these collaborations included the identification and validation of a series of small molecules that interact with SMAD4 and the development of two web applications, HTSDSF Explorer, used to analyse screening plates (available for public use; doi: 10.1016/j.jmb.2021.167372), and TPPU_DSF, an application to calculate thermodynamic parameters using DSF data (available for public use; doi: 10.1016/j.jmb.2024.168519).
Going forward, Maria plans to characterise the identified target–hit interactions using structural biology techniques, and the best hits will be validated in relevant cell lines and animal models. With the new molecules that resulted from these EU-OPENSCREEN-facilitated collaborations, Maria hopes to not only gain clarity on the TGF-β pathway in health and disease, but also to progress towards better therapeutics for patients with cancer and rare diseases.
In early 2024, Maria was awarded additional funding for her work through the first call on “advancing personalised Oncology” launched by the canSERV project (https://www.canserv.eu/), funded under the EU’s Horizon Europe Research and Innovation programme (Grant Agreement No. 101058620). This new project will allow her group to progress their research even further through access to advanced profiling services within the EU-OPENSCREEN consortium, with Dr Geir Klinkenberg at SINTEF, Norway, and Dr Mabel Loza of the BioFarma Group at the University of Santiago de Compostela, Spain.
