Nimbus (Italy)

The BRG/Brahma-associated factors (BAF or mSWI/SNF) family of chromatin remodeling complexes are critical regulators of gene expression and are major determinants of cancer and other diseases. Two paralog ATPases, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively), provide the enzymatic activity required for chromatin remodeling. Here, we discover and characterize a novel series of compounds that potently and selectively inhibit SMARCA4/SMARCA2. Mutational and biochemical studies demonstrate that these inhibitors act through a unique mode of inhibition, distinct from reported SMARCA4/SMARCA2 inhibitors. Across a range of cancer cell lines, SMARCA4/SMARCA2 inhibition resulted in lineage-specific changes in chromatin accessibility at binding sites for key transcription factors (TFs). In uveal melanoma (UM), BAF inhibition resulted in loss of enhancer occupancy of SOX10 and MITF, two essential TFs, leading to down-regulation of the melanocytic gene expression program. In a mouse xenograft model of UM, SMARCA4/SMARCA2 inhibition was well tolerated and resulted in dose-dependent tumor regression correlating with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat TF-dependent cancers.

Abstract The de novo pyrimidine biosynthetic pathway is an inducible cellular program which allows the rapid synthesis of pyrimidine nucleotides in proliferating cells, and the final rate-limiting step is catalyzed by cytidine triphosphate synthase (CTPS1 or CTPS2). A CTPS1 loss-of-function mutation in humans has illustrated the essential and non-redundant role of CTPS1 in activated lymphocyte proliferation. Therefore, selective CTPS1 inhibition is an attractive approach to specifically target pathological immune activity in autoimmune and inflammatory disease. Using cryo-EM and structure-based drug design, we have identified a series of potent, orally bioavailable, CTPS1-specific inhibitors, exemplified by the compound NTX-871. In-vitro, NTX-871 significantly inhibits the proliferation of T-cell derived lines and activated primary T-cells. These inhibitory effects are reversed by the addition of exogenous cytidine, illustrating the specificity of NTX-871 for CTPS1 and the de novo pyrimidine synthesis program. NTX-871 was also tested in several mouse in-vivo PD and autoimmune disease models. Oral dosing of NTX-871 significantly reduced T-cell proliferation in an ovalbumin-induced T-cell proliferation model, and QD or BID dosing of NTX-871 significantly improved disease phenotypes in models of delayed-type hypersensitivity, collagen-induced arthritis, and experimental autoimmune encephalomyelitis.

The modern aeronautical scenario has welcomed the massive diffusion of new key elements, including the Remote Piloted Aircraft Systems (RPAS), initially used for military purposes only. The current decade has seen RPAS ready to become a new airspace user in a large variety of civilian applications. Although RPAS can currently only be flown into segregated airspaces, due to national and international Flight Aviation Authorities′ (FAAs) constraints, they represent a remarkable potential growth in terms of development and economic investments for aviation. Full RPAS development will only happen when flight into non-segregated airspaces is authorized, as for manned civil and military aircraft. The preliminary requirement for disclosing the airspace to RPAS is the implementation of an ad hoc Safety Management System (SMS), as prescribed by ICAO, for every aeronautical operator. This issue arises in the context of the ongoing restructuring of airspaces management, according to SESAR-JU in Europe and NextGen in the USA (SESAR-JU has defined how RPAS research should be conducted in SESAR 2020, all in accordance with the 2015 European ATM Master Plan). This paper provides the basis to implement a risk model and general procedures/methodologies to investigate RPAS safety, according to the operational scenarios defined by EASA (European Aviation Safety Agency). The study is based on results achieved by multiple-RPAS experimental flights, performed within the RAID (RPAS-ATM Integration Demonstration) project.

<div class="section abstract"><div class="htmlview paragraph">In this paper the regulatory and standardization aspects regarding the light UAV segment are described reporting main steps and activities carried out during the FP7 European SkyMedia funded project.</div><div class="htmlview paragraph">With respect to the Unmanned Aircraft Vehicle regulation achievements, a detailed process conducted beside the Italian Flight Regulation Authority (ENAC) is reported emphasizing the key points that led to receive multiple Permit to Fly for Nimbus novel hybrid UAV platform, the first case in Italy in the category of “light UAV”.</div><div class="htmlview paragraph">With specific reference to the UAV segment, after showing the complex procedure defined with such Authority to receive authorization to fly for project final demo, some light on the future perspectives for light UAV regulation will be provided underlining efforts and contributions to define a clear track on the UAV development in civil applications.</div><div class="htmlview paragraph">In this context, further experimental procedures can be implemented in the next future to extend such procedures to other motivated cases likes, for example, national security or similar civil protection operations. Since nowadays a special regulation is missing in this field, this activity can provide a reference and some useful information on the key elements that will be evaluated by national flight authority in the process of issuing the permit to fly to light UAS in other countries.</div></div>

Thomas, D.; Butler, K.; Taylor, L.; le Blanc, P.; Griffith, B.; Kormos, R.; Borovetz, H.; Litwak, P.; Kameneva, M.; Choi, S.; Burgreen, G.; Wu, J.; Antaki, J. Author Information

Macha, M.; Litwak, P.; Yamazaki, K.; Kameneva, M.; Kerrigan, J.; Antaki, J; Borovetz, H.; Butler, K.*; Thomas, D.*; Taylor, L.*; Kormos, R.; Griffith, B. Author Information

Macha, M.; Litwak, P.; Yamazaki, K.; Kameneva, M.; Kerrigan, J.; Antaki, J; Borovetz, H.; Butler, K.; Thomas, D.; Taylor, L.; Kormos, R.; Griffith, B. Author Information