Informe Técnico de las actividades realizadas para el PCE 2017 0032

MIEMBROS DEL NODO SCREENING-SORIA, G; PAVIOLO NS; MIEMBROS DEL NODO DE PRODUCTOS NATURALES- CARPINELLA, MC; MIEMBROS DEL NODO DE VALIDACIÓN-GOTTIFREDI, V

2019-06-12/2019-06-12

Biológica

Salud humana

The goal of this project is to identify and validate novel druggable targets that can be used to induce synthetic lethality in cancer cells with defective Homologous Recombination (HR) repair. To achieve this goal, we will validate a set of synthetic lethal inducers identified in a library of natural products and natural products-like compounds from GSK: as mentioned before we have already performed screenings using a 688 kinase inhibitors library and a 13K library of natural products from GSK. Although we have been successful in identifying and validating two novel targets (PLK1, ROCK), the number of confirmed hits identified in the last screening (22 compounds) exceeds our capacity to finalize their validation with our current human resources and in the time-frame originally allocated for the project. With the remaining funds and the current manpower of our consortium we estimate that we will be able to complete the validation of a maximum of 2 hits. Therefore, the specific aim of this proposal is to complete the validation of the 20 remaining active compounds to promote the identification of as many novel targets as possible. The validation pipeline will include an initial validation using BRCA proficient and deficient cell lines derived from patients, studies of genomic and cytogenetic stability, comparison and combination with PARP inhibitors and transcriptional and proteomic studies.