Suchergebnisse

In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development. ; The National University of Quilmes (grant 53/1004 to DG), the National Council of Scientific and Technical Research (CONICET) (grant PIP 2015-2017 to PL) and Chemo-Romikin supported this study. NG is research fellow, and GC, PL, and DG are members of the National Research Council (CONICET, Argentina). XB is supported by grants from the Castilla–León Government (CLC–2017–01), the Spanish Ministry of Science, Innovation and Universities (MSIU) (RTI2018–096481–B–I00), and the Spanish Association against Cancer (GC16173472GARC). XB's institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla–León Government (CLC–2017–01). SR-F and LL-M contracts have been supported by funding from the MISIU (SR-F, BES–2013–063573) and the Spanish Ministry of Education, Culture and Sports (LL-M, FPU13/02923), respectively. JR-V's contract has been supported by both the CIBERONC and the Spanish Association against Cancer. Both Spanish and Castilla–León government–associated funding is partially supported by the European Regional Development Fund. ; Peer reviewed