Marie Sklodowska- Curie Action Individual Fellowship (IF)

Brief Description of the Group/Department

The Small Molecule Drug Discovery Platform is dedicated to early Drug Discovery activities in the fields of Cardiovascular Sciences, Neurosciences, Hepatology and Oncology. Our mission is to discover and to develop pharmacological tools for in vivo validation of novel hypothesis and targets/pathways identified by CIMA’s Basic Research Group, and to do so by working in close collaboration with these groups. Overall, the translational component of the basic and applied research carried at CIMA is pursued.

Our lab’s standard workflow involves the identification of chemical probes for initial validation of the targets, either by running virtual screening campaigns of commercial compounds or by de novo design and synthesis of novel compounds followed by biochemical / cellular profiling. After hit confirmation, medicinal chemistry efforts are directed towards the optimization of these probes into leads for in vivo efficacy/safety validation in appropriate animal models. We are responsible for the compound acquisition, design, synthesis, logistics, biochemical, cellular (also in collaboration with CIMA’s groups), preliminary ADME (cytotoxicity, permeability,…) and pharmacokinetic profiling. Achieving intellectual property (use- and more importantly product-) is pursued.

In parallel, due to the multidisciplinary nature of our team, we participate in different CIMA’s projects in assays development, target identification/validation and bioanalysis.

Research/ Project Description

Currently, we are strongly focused on the development of epigenetic therapies as an alternative to standard oncological treatments. Of note, this novel therapeutic strategy is not only restricted to the treatment of cancer; its efficacy in the treatment of cognitive disorders, metabolic alterations and autoimmune diseases is also being investigated.

We recently reported the discovery of a novel compound (CM-272) as a first-in-class inhibitor targeting the G9a and DNMTs methyltransferase activity with nanomolar potency (Nat. Commun. 2017; doi: 10.1038/ncomms15424). In vitro treatment of different haematological neoplasia with CM-272 inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significatly prolongs survival of acute myeloid leukaemia, acute lymphoblastic leukaemia and diffuse large B-cell lymphoma xenogeneic models. The in vivo efficacy of CM-272 in alternative cancers (e.g. solid tumors) is currently being investigaged, alone or in combination with other chemotherapeutic agents. In this regard, the candidate would support the design of in vivo efficacy experiments (e.g. dosage administration for combination studies, compound quantification in the targeted tissue…).

We are developing a second generation of epigenetic inhibitors (undisclosed target), having promising biological activity. The optimization of these compounds is on-going and the candidate will participate in all aspects concerning LC-MS/MS bioanalysis (e.g. PK profiling, proposal of alternative formulations, microsomal stability assays…) and will be integrated in the decision work-flow to progress compound candidates for in vivo efficacy testing.

LC-MS/MS bioanalysis contribution in starting and back-up projects is also contemplated.

Who can apply?

     General requirements

At the deadline for the submission of proposals (12/09/2018), researchers (*):

• Shall be in possession of a doctoral degree or have at least four years of full-time equivalent research experience.
• Must not have resided or carried out their main activities in the country of Spain for more than 12 months in the 3 years (36 months) immediately prior to the abovementioned deadline.

    Specific requirements

• A Curriculum Vitae 
• Summary presentation of the candidate’s research proposal and expertise that he/she would bring to the institution (maximum extension determined by the supervisor. According to the MSCA Programme, the maximum length of a proposal is 10 pages, excluding the CV of the researcher and the annexes)
• A motivation letter (1 page)
• Contact information of 2 referees