Abstract A32: Gaps and opportunities for RASopathies: Use of new tools to make the right choice in target and compound selection

“RASopathies” are a class of developmental disorders caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. Each syndrome exhibits different phenotypic features, though there are many overlapping features among syndromes, including characteristic facial features, cardiac defects, cutaneous abnormalities, autism, learning disabilities and a predisposition to malignancies. Neurofibromatosis type 1 (NF1) has been more extensively studied than the other syndromes and today 11 clinical trials are ongoing for NF1 versus 3 in all other RASopathies. In the last couple of years a few studies were published which directly connected the molecular mechanisms of these diseases to each other, creating a new opportunity to cross-validate the effects of modulating the RAS pathway at different stages and with different tools, and providing new overlapping strategies which could also benefit less studied syndromes. We recently acquired in-house capabilities to access MetaCore and Integrity databases to help in the process of data mining and compound selection. We applied these capabilities in a multi-tiered approach to compare NF1 with Noonan Syndrome (NS). First, we analyzed the molecular profiles of these two RASopathies using MetaCore and zeroed in on a well-known common molecular target, MEK. Among the large number of MEK inhibitors now in development, an analysis of these agents has been made with the use of the database to compare the different chemical classes of inhibitors and analyse properties, opportunities and redundancies among these compounds. The same approach will be then applied to try to identify a novel drug target in common in NF1 and NS. For this new target, an analysis of available drugs will be made to try to identify the best candidate/s which could be explored for in vitro or in vivo testing or as a proof-of-concept. Combining the capabilities of bioinformatic analysis and chemical analysis, a more informed drug choice for screening and/or preclinical testing can be done on the basis of detailed information on drugs and interconnections of targets/pathways. This approach, taking into account the various aspects of a particular model or disease, will attempt to accelerate research by allowing the selection of the most suitable compounds for a particular experiment, allowing for more informed choices. Citation Format: Salvatore La Rosa, Pamela Knight, Patrice Pancza, Kimberly Scobie, Annette Bakker. Gaps and opportunities for RASopathies: Use of new tools to make the right choice in target and compound selection. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A32. doi: 10.1158/1557-3125.RASONC14-A32