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Experimental Therapeutics Programme

Director: Joaquín Pastor
Secretary: Natalia Catalá

The Experimental Therapeutics Programme (ETP) serves as a bridge between basic research results in cancer biology (i.e. novel therapeutic targets and hypothesis) and the development of potential antitumour drugs. This is achieved through the application of early drug discovery phases in order to obtain advanced compounds ready for in vivo Proof of Concept (PoC) studies. These molecules are subject to standard in vivo characterisation by our Group as well as more detailed studies at the basic research labs where the therapeutic target emerged. The best candidates obtained by applying this operating model are then ready for clinical development in partnership with pharmaceutical companies. ETP also helps in the validation of innovative targets by providing high quality chemical probes to the basic research laboratories. Moreover, we participate in the identification of novel targets (for projects based on phenotypic screenings) by using our expertise in target deconvolution phases, including the development of affinity probes.

Currently, the most advanced targeted project is dedicated to CDK8 inhibitors. In this project, we have selected our first leads, ETP-27 and ETP-93, which have yielded positive results in efficacy studies in haematological cancer xenograft models after oral administration. Interestingly, our chemical series displays dual CDK8/Haspin or specific CDK8 activities depending on the substitution pattern. ETP-18 represents a highly selective CDK8 inhibitor, which is undergoing pharmacokinetic (PK) studies.

Other targeted projects dedicated to the kinases Haspin and Mastl (in collaboration with Marcos Malumbres, CNIO Cell Division and Cancer Group) are focused on the discovery and generation, for the first time, of specific chemical probes to interrogate their therapeutic potential. During 2017, we generated a chemical series of Haspin inhibitors by application of structure-based design strategies. Compound ETP-949 proved to be a low nanomolar and highly specific inhibitor after profiling against more than 450 kinase targets. These compounds will serve as important tools to study the therapeutic potential of the pharmacological inhibition of this mitotic and epigenetic kinase. We have continued with the exploration of several previously identified families of Mastl inhibitors ; we have now generated a preliminary SAR (Structure Activity Relationship) and have improved their potency up to a low nanomolar range. Currently, we are working to control their selectivity.

On the other hand, we are collaborating with the CNIO Telomeres and Telomerase Group (Maria Blasco) in the development of TRF1 target for cancer therapy ; in this context, we have contributed to the discovery of novel TRF1 inhibitors. During 2017, ETP has helped to decipher the connection of the PI3K/AKT axis as a modulator of TRF1 localisation at telomeres by using a chemical biology approach. Moreover, we have been able to identify other potential cell signalling pathways as TRF1 regulators, currently under investigation, after the screening of our ETP-library of antitumour compounds. Furthermore, we are still working on the deconvolution of the molecular mechanism of a previously identified chemical series. Interestingly, several affinity probes have been prepared and will be used for cell localisation and pull down experiments in order to shed light on the mechanism of action of these compounds.

ETP has collaborated in a project dedicated to the discovery of novel targets and modulators against Cancer Stem Cells (Manuel Serrano). Our team previously designed and synthesised affinity probes to help in target deconvolution studies. The use of these probes has enabled the identification of a potential mechanism of action, which is currently under in vivo validation studies.

Finally, we have also collaborated with other CNIO basic researchers to carry out several screening campaigns, both targeted and phenotypic. For instance, to discover novel senolytic compounds (Manuel Serrano), brain metastasis blockers (Manuel Valiente), mTOR pathway modulators with unexplored mechanisms of action (Alejo Efeyan), alternative Ras pathway modulators (Óscar Fernández-Capetillo) and treatments for malignant peripheral nerve sheath tumours (MPNST) (Héctor Peinado), bladder cancer (Francisco Real), and EGFR deficient mutant KRas mouse tumours (Mariano Barbacid/Carmen Guerra). ETP-MedChem has also contributed with the synthesis of valuable tool compounds for research in the field of lung fibrosis (Erwin Wagner) and cell haploidy stabilisation (Óscar Fernández-Capetillo).