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User Story: Dr Eulàlia de Nadal, IRB Barcelona
Identifying phosphomimetic RB modulators
Access to the EU-OPENSCREEN research infrastructure was instrumental for our project. It provided us with a vast chemical library, high-throughput screening services, and the indispensable support of a medicinal chemist.
Eulàlia de Nadal
User:
Dr Eulàlia de Nadal, Affiliated Group Leader in the Mechanisms of Disease Unit, IRB Barcelona, Barcelona, Spain
EU-OPENSCREEN screening partner site:
Dr Sergey Kuznetsov, Dr Jani Saarela, Prof. Päivi Tammela, High Throughput Biomedicine Unit, Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland
EU-OPENSCREEN chemistry partner site:
Prof. Aigars Jirgensons, Latvian Institute of Organic Synthesis (LIOS), Riga, Latvia
Cancer pathogenesis can be triggered by manifold causes, but all ultimately affect the same underlying process: the cell cycle. Aberrant regulation of the cell cycle can lead to uncontrolled cell division and, ultimately, the growth of a tumour. The research group of EU-OPENSCREEN user Dr Eulàlia de Nadal have identified key regulatory mechanisms of this cycle and, with the support of EU-OPENSCREEN partner sites, have pinpointed potential molecules to pharmaceutically regulate these targets.
When under stress, cells trigger an adaptive response to maximise survival. This response, coordinated by stress-activated protein kinases (SAPKs), essentially rewires the cells’ normal functions. SAPK activity alters several aspects of cellular physiology, from metabolism to gene expression, and even halts cell growth.
Understanding these SAPK-mediated events is the research focus of the group of Dr Eulàlia de Nadal, co-led with Dr Francesc Posas, both of the Mechanisms of Disease Unit at IRB Barcelona, Barcelona, Spain. Her group investigates these events in yeast and mammalian cells during adaptation to stress, a process driven by the highly conserved SAPKs Hog1/p38. Through this lens, Eulàlia’s group have characterised alternative phosphorylation on RB1, a cell cycle repressor, that overrides regular cell growth mechanisms (Figure 1), thereby laying the groundwork for their current aim: to chemically replicate the stress-dependent mechanisms of cell cycle blockage.
Under normal conditions, members of the cell cycle-regulating cyclin-dependent kinase (CDK) family are essential for keeping cell division in check – a function achieved through phosphorylation. However, when CDKs are hyperactivated, several downstream effects are triggered which can contribute to pathological cell division. One such effect is the inactivation of the tumour suppressor protein retinoblastoma (Rb), a critical modulator the G1/S cell cycle transition.
Working with Rb protein, Eulàlia’s group have previously determined that the SAPK p38 can actually modulate Rb such that it is immune to the inhibitory effects of aberrant CDK activity. They achieved this by identifying and mapping p38-dependent phosphorylations that repress the expression of cell cycle-related genes, which in turn delay cell cycle progression even with high CDK activity. Eulàlia’s group now aim to progress this discovery into a viable anti-tumour therapeutic in patients with the mutations responsible for CDK hyperactivity and consequent Rb repression.
To achieve this aim, Eulàlia’s group generated and optimised a cell-based assay to identify small compounds that mimic p38-dependent regulatory events. Under the EU-funded project EU-OPENSCREEN-DRIVE (Grant Agreement No. 823893), they then received access to two branches of the EU-OPENSCREEN service catalogue to advance this project. In the first phase, they collaborated with the FIMM High Throughput Biomedicine Unit (University of Helsinki; www.helsinki.fi/high-throughput-biomedicine), an EU-OPENSCREEN screening partner site led by Prof. Päivi Tammela, to conduct an initial pilot screen and a primary high-throughput screen (HTS) against EU-OPENSCREEN's European Chemical Biology Library (ECBL) as well as hit validation. Then, in a second phase, they leveraged the medicinal chemistry services provided by Prof. Aigars Jirgensons of partner site the Latvian Institute of Organic Synthesis (LIOS) to prioritise their selection of the most promising candidate compounds.
Through her engagement with both EU-OPENSCREEN partner sites, Eulàlia reported that her group gained valuable access to the specialised resources needed to advance their study and uncover potential cell cycle modulators. As next steps, she plans to involve secondary validation to confirm the initial findings of the primary screening and conduct additional orthogonal assays, enabling further characterisation of potential hits.
