Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease with most common manifestation being the development of bilateral schwannomas of the 8th cranial nerve (Vestibular schwannoma). The NF2 tumor suppressor gene encodes for a 69-kDa protein called Merlin, implicated in the regulation of a number of signaling pathways, including those regulated by small G-proteins and the Hippo-YAP signaling pathway [2]. Although our understanding of the molecular mechanisms underlying NF2 has significantly improved over the past 2 decades, effective therapies remain lacking for this disease. Clearly, there is an urgent need to develop therapeutic options for NF2 patients. Importantly, we have recently demonstrated that YAP is required for NF2-null Schwann cell viability and proliferation, thus implicating YAP as a therapeutic target in NF2. The Hippo pathway is comprised of a kinase cascade that ultimately phosphorylates and inhibits the function of the transcriptional co-activator Yes-associated protein (YAP), as phospho-YAP is sequestered in the cytoplasm via its interactions with 14-3-3 proteins. In the nucleus YAP can function as a co-activator of a number of different transcription factors. Significantly, the oncogenic activities of YAP appear to be mediated primarily through interaction with the TEA-Domain transcription factors (TEAD1-4). Binding of YAP to TEADs induces expression of proliferative and anti-apoptotic genes that function as central effectors regulating cell fate, proliferation and organ size control, during development and normal physiological conditions. Systematic efforts to obtain inhibitors of YAP function have been limited in scope and previously identified inhibitors lack potency and specificity. To obtain selective inhibitors of YAP?s oncogenic function we focused on small molecules that disrupt the interaction between YAP and the TEADs and implemented an in silico screening approach, employing the known structure of the YAP-TEAD interface. These efforts led to identification of a number of hits, demonstrating strong activity in vitro and in cell-based models. Thus, our goal is to optimize small-molecule inhibitors of TEAD-YAP into probes that will be used to inhibit the function of YAP in vivo and determine the feasibility of targeting YAP as an anti-neoplastic strategy in NF2. In the R21 phase we will improve potency and pharmacokinetic properties of the identified YAP-TEAD inhibitors. The benchmark for transition to the R33 phase will be attainment of probe/s possessing properties required for in vivo assessment, as described in the proposal. In the R33 phase highly potent and increasingly optimized inhibitors will be assessed in cell-based models and in vivo models to assess efficacy of select optimized leads in inhibiting YAP function in vivo and tumor growth in models of NF2.
Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease with most common manifestation being the development of bilateral schwannomas of the 8th cranial nerve (Vestibular schwannoma). Although our understanding of the molecular mechanisms underlying NF2 has significantly improved over the past 2 decades, effective therapies remain lacking for this disease and there is an urgent need to develop therapeutic options for patients. Recent data implicates YAP as a therapeutic target in NF2 and we have identified a number of hits that demonstrate strong activity in vitro and in cell-based models of NF2; therefore, our goals in this proposal are to develop these small-molecule inhibitors into probes that will be used to inhibit YAP in vivo and establish the feasibility of targeting YAP as a therapeutic approach for NF2.
