Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease with the most common manifestation being development of bilateral schwannomas of the 8th cranial nerve (Vestibular schwannoma). The majority of NF2 patients develop additional tumors throughout the nervous system, including schwannomas, meningiomas and ependymomas, causing severe morbidity and early mortality. The NF2 tumor suppressor gene encodes for a 69-kDa protein called Merlin, implicated in the regulation of a number of signaling pathways, such as those regulated by small G-proteins and the Hippo-YAP signaling pathway. Although our understanding of the molecular mechanisms underlying NF2 has improved over the past two decades, effective therapies remain lacking. To date, systematic efforts to identify therapeutic agents for NF2 have demonstrated limited success, resulting in identification of a small number of candidates that displayed minimal selectivity towards NF2-deficient cells. Arguably, the reasons for this limited success stem from a number of factors including the fact these efforts relied on approaches utilizing traditional screening assays performed with cells plated on plastic dishes, in 2- dimensional (2D) monolayer formats. These conditions poorly reflect the environment cells experience in vivo. In addition, previous screens were performed against a small collection of compounds that were pre-selected based on drug-likeness, known pharmacology, regulatory status, etc. Thus, only limited chemical space has been explored in these efforts. Our long-term goals are to identify small molecules that selectively inhibit NF2-null Schwann cells and optimize these into lead molecules that will be developed into therapeutic agents. Towards this goal we will implement a screening campaign that incorporates a number of innovations that we already demonstrated to dramatically improve discovery efforts. We hypothesize that the proposed research campaign will identify pharmacologically tractable targets/pathways in NF2-null cells, which will be developed as leads for therapeutic development.