Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates.

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Rapid generation of a novel DPP-4 inhibitor with long-acting properties: SAR study and PK/PD evaluation.

Drug compliance is critical for patients with chronic diseases such as diabetes. In our continuous effort to find better glucose-lowering agents, an exploration for long-acting DPP-4 inhibitors had been launched. Based on our previously reported compounds bearing a pyrrolopyrimidine scaffold, the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) with pharmacokinetic superiority was rapidly determined. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which a ß-substitution gave a better DPP-4 affinity. In depth evaluation of the pyrrole ring ß position identified a highly potent compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated similar or even slightly better sustained DPP-4 inhibition for compounds 4a and 12a compared with the first marketed once-weekly drug trelagliptin in this category, indicating that improvements to DPP-4 inhibitory activity or pharmacokinetic profile might be feasible ways to rapidly generate long-acting DPP-4 inhibitors.

Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's Disease Models.

Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both ß amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents.

Identification of aminopyridazine-derived antineuroinflammatory agents effective in an Alzheimer's mouse model.

Targeting neuroinflammation may be a new strategy to combat Alzheimer's disease. An aminopyridazine 1b previously reported as a novel antineuroinflammatory agent was considered to have a potential therapeutic effect for Alzheimer's disease. In this study, we further explored the chemical space to identify more potent antineuroinflammatory agents and validate their in vivo efficacy in an animal model. Compound 14 was finally identified as an effective agent with comparable in vivo efficacy to the marketed drug donepezil in counteracting spatial learning and working memory impairment in an Aß-induced Alzheimer's mouse model.

Different effects of scopolamine on the retrieval of spatial memory and fear memory.

Retrieval of memory is fundamental for our life as individuals. The participation of cholinergic system in memory consolidation process has been extensively studied, but there are few data concerning the function of this system in memory retrieval process. In the current study, we inject non-selective muscarinic antagonist scopolamine peripherally 20 min before training or testing to see whether cholinergic modulation has effects on the acquisition or retrieval of spatial memory by water maze task and fear memory by inhibitory avoidance task. We find that the cholinergic system is essential for the acquisition of both spatial memory and fear memory. As for the memory retrieval, the cholinergic system has a positive role in the retrieval of spatial memory, because mice injected with scopolamine 20 min before the testing in the water maze show impaired spatial memory retrieval. Whereas injection of scopolamine 20 min before the testing in the inhibitory avoidance task does not cause memory retrieval deficits. That indicates the cholinergic system is not essential for the retrieval of fear memory.

Molecular properties and CYP2D6 substrates: central nervous system therapeutics case study and pattern analysis of a substrate database.

CYP2D6 substrate status is a critical Go/No Go decision criteria in central nervous system (CNS) drug discovery efforts because the polymorphic nature of CYP2D6 can lead to variable patient safety and drug efficacy. In addition, CYP2D6 is disproportionately involved in the metabolism of CNS drugs compared with other drug classes. Therefore, identifying trends in small molecule properties of CNS-penetrant compounds that can help discriminate potential CYP2D6 substrates from nonsubstrates would allow additional prioritization in the synthesis and biological evaluation of new therapeutic candidates. We report here the conversion of the CNS drug minaprine from substrate to nonsubstrate, as well as the conversion of the related CNS drug minozac from nonsubstrate to substrate, through the use of analog synthesis and CYP2D6 enzyme kinetic analyses. No single molecular property strongly correlated with substrate status for this 3-amino-4-methyl-6-phenylpyridazine scaffold, although molecular volume and charge appeared to be indirectly related. A parsed database of CYP2D6 substrates across diverse chemical structures was assembled and analyzed for physical property trends correlating with substrate status. We found that a complex interplay of properties influenced CYP2D6 substrate status and that the particular chemical scaffold affects which properties are most prominent. The results also identified an unexpected issue in CNS drug discovery, in that some property trends correlative with CYP2D6 substrates overlap previously reported properties that correlate with CNS penetrance. These results suggest the need for a careful balance in the design and synthesis of new CNS therapeutic candidates to avoid CYP2D6 substrate status while maintaining CNS penetrance.