Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.

Lessons learnt in photocatalysis - the influence of solvent polarity and the photostability of the photocatalyst.

Herein, we show that there is significant variation in both the triplet energies and redox properties of photocatalysts as a function of solvent based on a study of eight PCs in four solvents of varying polarity. A range of photocatalytic electron and energy transfer reactions were investigated using a subset of the PCs. For the photoredox reactions, the yields are not correlated with solvent polarity. Instead, when the PC could promote the formation of the target product, we observed photodegradation for all PCs across all solvents, something that is rarely investigated in the literature. This, therefore, makes it difficult to ascertain whether the parent PC and/or the photodegraded product is responsible for the photochemistry, or indeed, whether photodegradation is actually detrimental to the reaction yield. Conversely, the PCs were found to be photostable for energy transfer reactions; however, yields were not correlated to the triplet energies of the PCs, highlighting that triplet energies alone are not a suitable descriptor to discriminate the performance between PCs in photoinduced energy transfer processes.

A fast machine learning dataloader for epigenetic tracks from BigWig files.

SUMMARY: We created bigwig-loader, a data-loader for epigenetic profiles from BigWig files that decompresses and processes information for multiple intervals from multiple BigWig files in parallel. This is an access pattern needed to create training batches for typical machine learning models on epigenetics data. Using a new codec, the decompression can be done on a graphical processing unit (GPU) making it fast enough to create the training batches during training, mitigating the need for saving preprocessed training examples to disk. AVAILABILITY AND IMPLEMENTATION: The bigwig-loader installation instructions and source code can be accessed at https://github.com/pfizer-opensource/bigwig-loader.

Structural Control of Highly Efficient Thermally Activated Delayed Fluorescence in Carbene Zinc(II) Dithiolates.

Luminescent metal complexes based on earth abundant elements are a valuable target to substitute 4d/5d transition metal complexes as triplet emitters in advanced photonic applications. Whereas CuI complexes have been thoroughly investigated in the last two decades for this purpose, no structure-property-relationships for efficient luminescence involving triplet excited states from ZnII complexes are established. Herein, we report on the design of monomeric carbene zinc(II) dithiolates (CZT) featuring a donor-acceptor-motif that leads to highly efficient thermally activated delayed fluorescence (TADF) with for ZnII compounds unprecedented radiative rate constants kTADF =1.2×106  s-1 at 297 K. Our high-level DFT/MRCI calculations revealed that the relative orientation of the ligands involved in the ligand-to-ligand charge transfer (1/3 LLCT) states is paramount to control the TADF process. Specifically, a dihedral angle of 36-40° leads to very efficient reverse intersystem-crossing (rISC) on the order of 109  s-1 due to spin-orbit coupling (SOC) mediated by the sulfur atoms in combination with a small ΔES1-T1 of ca. 56 meV.

Synthesis, Structural Characterization, and Phosphorescence Properties of Trigonal Zn(II) Carbene Complexes.

The sterically demanding N-heterocyclic carbene ITr (N,N'-bis(triphenylmethyl)imidazolylidene) was employed for the preparation of novel trigonal zinc(II) complexes of the type [ZnX2(ITr)] [X = Cl (1), Br (2), and I (3)], for which the low coordination mode was confirmed in both solution and solid state. Because of the atypical coordination geometry, the reactivity of 1-3 was studied in detail using partial or exhaustive halide exchange and halide abstraction reactions to access [ZnLCl(ITr)] [L = carbazolate (4), 3,6-di-tert-butyl-carbazolate (5), phenoxazine (6), and phenothiazine (7)], [Zn(bdt)(ITr)] (bdt = benzene-1,2-dithiolate) (8), and cationic [Zn(µ2-X)(ITr)]2[B(C6F5)4]2 [X = Cl (9), Br (10), and I (11)], all of which were isolated and structurally characterized. Importantly, for all complexes 4-11, the trigonal coordination environment of the ZnII ion is maintained, demonstrating a highly stabilizing effect due to the steric demand of the ITr ligand, which protects the metal center from further ligand association. In addition, complexes 1-3 and 8-11 show long-lived luminescence from triplet excited states in the solid state at room temperature, according to our photophysical studies. Our quantum chemical density functional theory/multireference configuration interaction (DFT/MRCI) calculations reveal that the phosphorescence of 8 originates from a locally excited triplet state on the bdt ligand. They further suggest that the phenyl substituents of ITr are photochemically not innocent but can coordinate to the electron-deficient metal center of this trigonal complex in the excited state.

Towards Fast Circularly Polarized Luminescence in 2-Coordinate Chiral Mechanochromic Copper(I) Carbene Complexes.

A series of chiral mechanochromic copper(I) cAAC (cAAC=cyclic (alkyl)(amino)carbene) complexes with a variety of amide ligands have been studied with regard to their photophysical and chiroptical properties to elucidate structure-property relationships for the design of efficient triplet exciton emitters exhibiting circularly polarized luminescence. Depending on the environment, which determines the excited state energies, either thermally activated delayed fluorescence (TADF) from 1/3 LLCT states or phosphorescence from 3 LLCT/LC states occurs. However, neither chiral moieties at the carbene nor at the carbazolate ligands provide detectable luminescence dissymmetries glum . An exception is [Cu(phenoxazinyl)(cAAC)], showing orange to deep red TADF with λmax =601-715 nm in solution, powders and in PMMA. In this case, the amide ligand can undergo distortions in the excited state. This design motif leads to the first linear, non-aggregated CPL-active copper(I) complex with glum of -3.4 ⋅ 10-3 combined with a high radiative rate constant of 6.7 ⋅ 105  s-1 .

Cellenium-a scalable and interactive visual analytics app for exploring multimodal single-cell data.

SUMMARY: Multimodal single-cell sequencing data provide detailed views into the molecular biology of cells. To allow for interactive analyses of such rich data and to readily derive insights from it, new analysis solutions are required. In this work, we present Cellenium, our new scalable visual analytics web application that enables users to semantically integrate and organize all their single-cell RNA-, ATAC-, and CITE-sequencing studies. Users can then find relevant studies and analyze single-cell data within and across studies. An interactive cell annotation feature allows for adding user-defined cell types. AVAILABILITY AND IMPLEMENTATION: Source code and documentation are freely available under an MIT license and are available on GitHub (https://github.com/Bayer-Group/cellenium). The server backend is implemented in PostgreSQL, Python 3, and GraphQL, the frontend is written in ReactJS, TypeScript, and Mantine css, and plots are generated using plotlyjs, seaborn, vega-lite, and nivo.rocks. The application is dockerized and can be deployed and orchestrated on a standard workstation via docker-compose.

Fast and Tunable Phosphorescence from Organic Ionic Crystals.

Crystalline diphosphonium iodides [MeR2 P-spacer-R2 Me]I with phenylene (1, 2), naphthalene (3, 4), biphenyl (5) and anthracene (6) as aromatic spacers, are photoemissive under ambient conditions. The emission colors (λem values from 550 to 880 nm) and intensities (Φem reaching 0.75) are defined by the composition and substitution geometry of the central conjugated chromophore motif, and the anion-π interactions. Time-resolved and variable-temperature luminescence studies suggest phosphorescence for all the titled compounds, which demonstrate observed lifetimes of 0.46-92.23 µs at 297 K. Radiative rate constants kr as high as 2.8×105  s-1 deduced for salts 1-3 were assigned to strong spin-orbit coupling enhanced by an external heavy atom effect arising from the anion-π charge-transfer character of the triplet excited state. These rates of anomalously fast metal-free phosphorescence are comparable to those of transition metal complexes and organic luminophores that utilize triplet excitons via a thermally activated delayed fluorescence mechanism, making such ionic luminophores a new paradigm for the design of photofunctional and responsive molecular materials.

From Terminal to Spiro-Phosphonium Acceptors, Remarkable Moieties to Develop Polyaromatic NIR Dyes.

Phosphonium-based compounds gain attention as promising photofunctional materials. As a contribution to the emerging field, we present a series of donor-acceptor ionic dyes, which were constructed by tailoring phosphonium (A) and extended π-NR2 (D) fragments to an anthracene framework. The alteration of the π-spacer of electron-donating substituents in species with terminal -+ PPh2 Me groups exhibits a long absorption wavelength up to λabs =527 nm in dichloromethane and shifted the emission to the near-infrared (NIR) region (λ=805 nm for thienyl aniline donor), although at low quantum yield (Φ<0.01). In turn, the introduction of a P-heterocyclic acceptor substantially narrowed the optical bandgap and improved the efficiency of fluorescence. In particular, the phospha-spiro moiety allowed to attain NIR emission (797 nm in dichloromethane) with fluorescence efficiency as high as Φ=0.12. The electron-accepting property of the phospha-spiro constituent outperformed that of the monocyclic and terminal phosphonium counterparts, illustrating a promising direction in the design of novel charge-transfer chromophores.

Mechano-Stimulus and Environment-Dependent Circularly Polarized TADF in Chiral Copper(I) Complexes and Their Application in OLEDs.

Molecular emitters that combine circularly polarized luminescence (CPL) and high radiative rate constants of the triplet exciton decay are highly attractive for electroluminescent devices (OLEDs) or next-generation photonic applications, such as spintronics, quantum computing, cryptography, or sensors. However, the design of such emitters is a major challenge because the criteria for enhancing these two properties are mutually exclusive. In this contribution, we show that enantiomerically pure {Cu(CbzR)[(S/R)-BINAP]} [R = H (1), 3,6-tBu (2)] are efficient thermally activated delayed fluorescence (TADF) emitters with high radiative rate constants of kTADF up to 3.1 × 105 s-1 from 1/3LLCT states according to our temperature-dependent time-resolved luminescence studies. The efficiency of the TADF process and emission wavelengths are highly sensitive to environmental hydrogen bonding of the ligands, which can be disrupted by grinding of the crystalline materials. The origin of this pronounced mechano-stimulus photophysical behavior is a thermal equilibrium between the 1/3LLCT states and a 3LC state of the BINAP ligand, which depends on the relative energetic order of the excited states and is prone to inter-ligand C-H···π interactions. The copper(I) complexes are also efficient CPL emitters displaying exceptional dissymmetry values glum of up to ±0.6 × 10-2 in THF solution and ±2.1 × 10-2 in the solid state. Importantly for application in electroluminescence devices, the C-H···π interactions can also be disrupted by employing sterically bulky matrices. Accordingly, we have investigated various matrix materials for successful implementation of the chiral copper(I) TADF emitters in proof-of-concept CP-OLEDs.

An Air- and Moisture-stable Zinc(II) Carbene Dithiolate Dimer Showing Fast Thermally Activated Delayed Fluorescence and Dexter Energy Transfer Catalysis.

A dimeric ZnII carbene complex featuring bridging and chelating benzene-1,2-dithiolate ligands is highly stable towards air and water. The donor-Zn-acceptor structure leads to visible light emission in the solid state, solution and polymer matrices with λmax between 577-657 nm and, for zinc(II) complexes, unusually high radiative rate constants for triplet exciton decay of up to kr =1.5×105  s-1 at room temperature. Variable temperature and DFT/MRCI studies show that a small energy gap between the 1/3 LL/LMCT states of only 79 meV is responsible for efficient thermally activated delayed fluorescence (TADF). Time-resolved luminescence and transient absorption studies confirm the occurrence of long-lived, dominantly ligand-to-ligand charge transfer excited states in solution, allowing for application in Dexter energy transfer photocatalysis.

Finding Design Principles of OLED Emitters through Theoretical Investigations of Zn(II) Carbene Complexes.

In this work, Zn(II) carbene complexes carrying a dianionic 1,2-dithiolbenzene (dtb) or 1,2-diolbenzene (dob) ligand were investigated regarding their suitability as organic light-emitting diode (OLED) emitter. For the optimization of the complexes, density functional-based methods were used and frequency analyses verified the obtained structures as minima. All calculations were carried out including a polarizable continuum model to mimic solvent-solute interactions. Multireference configuration interaction methods were used to determine excitation energies, spin-orbit couplings, and luminescence properties. Rate constants of spin-allowed and spin-forbidden transitions were calculated according to a Fermi golden rule expression. Using carbene ligands with varying σ-donor and π-acceptor strengths, the luminescence is found to be tunable from yellow to orange/red to deep red/near-infrared. The calculated intersystem crossing (ISC) time constants indicate thermally activated delayed fluorescence (TADF) to be the main decay channel. In contrast to many d10 coinage metal complexes, a parallel orientation of dtb or dob and the carbene ligand is found to be highly favorable. For the complexes with a cyclic (alkyl)(amino) carbene (CAAC) or cyclic (amino)(aryl) carbene (CAArC) ligand, the S1 and T1 states have ligand-to-ligand charge-transfer (LLCT) character and are energetically close. The complex with a classical N-heterocyclic carbene (NHC) ligand has S1 and T1 states with mixed ligand-to-metal charge-transfer (LMCT)/LLCT character and is a very rare example in which the zinc ion contributes to the excitation.

Synthesis and Photophysical Studies of Copper(I) CAAC Half-Sandwich Complexes as a Highly Modifiable Class of Emitters.

Cyclopentadienyls are well-known strong donor ligands and have been successfully employed in catalysis as they tolerate a variety of substituents to adjust their steric and electronic properties. Although such highly modifiable ligands are of great interest for luminescence and photocatalytic applications, studies of CpR-containing photoactive transition-metal complexes are quite rare. In this work, we present a structural, electrochemical, and first elaborated photophysical investigation of a series of copper(I) half-sandwich complexes bearing cyclic alkyl(amino)carbenes (CAACs) as chromophore ligands and compare them with [Cu(Cp)(IDipp)] and [Cu(Cp*)(IDipp)] bearing a traditional N-heterocyclic carbene. Furthermore, we present the first molecular structure derived from single-crystal X-ray diffraction of a copper(I) indenyl complex, which can be described as an η2 (σ, π)-coordination. The CuI half-sandwich complexes show blue-green to orange phosphorescence with a photoluminescence quantum yield of up to 59% and radiative rate constants kr of up to 4 × 104 s-1 in the solid state, depending on the substitution pattern of the CpR ligand. Our TD/DFT calculations suggest that the emitting excited states are of 3MLCT/LLCT character. We determined the excited-state lifetime of the CuI half-sandwich complexes in solution to be as long as 600 ns, which in combination with the large π-surface of the CpR ligands allows for Dexter energy transfer for photocatalytic applications. In addition, the chiroptical properties of chiral [Cu(Cp/Cp*)(CAACMenthone)] were studied and compared to [CuCl(CAACMenthone)], of which we demonstrate that its circular polarized luminescence is the result of excimer formation and not, as previously reported, attributed to the monomeric C1-symmetric structure.

Trigonal Copper(I) Complexes with Cyclic (Alkyl)(amino)carbene Ligands for Single-Photon Near-IR Triplet Emission.

Molecular near-IR (NIR) triplet-state emitters are of importance for the development of new, organic-electronics-based telecommunication technologies as optical fibers operating in the corresponding spectral bands allow for data transfer over much longer distances due to the significantly lower attenuation. However, achieving such low-energy triplet excited states with good radiative rate constants is very challenging, and studies regarding the single-photon emission of organometallics in this energy range are scarce. We have prepared a series of trigonal CuI CAAC complexes bearing chelating ligands with O, N, S, and Se donor atoms and studied their photophysical properties in this context. The compounds show weak low-energy absorption in solution between 400 and 500 nm due to mixed Cu → CAAC 1MLCT/LLCT states, resulting in yellow-green to orange appearance, which we have also correlated to the 15N NMR resonances of the π-accepting carbene ligand. In the solid state, phosphorescence from dominant 3(Cu → CAAC) CT states is observed at room temperature. The emission of the complexes is bathochromically shifted in comparison to structurally related linearly coordinated copper(I) CAAC complexes due to structural reorganization in the excited state to a T-shape. For [Cu(dbm)(CAACMe)], the broad phosphorescence with outstanding λmax = 760 nm tailors out to ca. 1100 nm and leads to its proof-of-concept application as a nonclassical single-photon light source, constituting key functional units for the implementation of tap-proof data transfer.

Synthesis and Fluorescence Studies of Diborene Coinage Metal Complexes.

Nine different coinage metal (Cu, Ag) π complexes of diborenes with various anionic diborene (aryl, heteroaryl) and metal substituents (Cl, Br, C6F5, C2SiMe3), stabilizing neutral donors (N-heterocyclic carbene = NHC, phosphine), configurations (cis/trans, acyclic/cyclic diborene), and charges (neutral, cationic) were synthesized and characterized by multinuclear NMR spectroscopy and X-ray crystallographic analyses. Their optical properties were investigated by UV-vis absorption and steady-state as well as time-resolved luminescence spectroscopy in solution and the solid state to gain insights into the excited-state behavior of this unusual class of photoactive compounds and to provide structure-property relationships. The structural and electronic modification of the (B═B)···M motif greatly influences not only the visible light absorption but also the photostability and quantum yields, which can reach high values of up to f = 0.42. The lifetimes are found in the nanosecond regime, providing estimated radiative rate constants over a wide range of kr = 1.3-14 × 107 s-1, indicative of fluorescence. Intersystem crossing (ISC) is sufficiently slow for prompt emission from the S1 state to be observed, while the spin-orbit coupling in the T1 state is too weak for phosphorescence to occur at room temperature. ISC can be accelerated, however, by modifying diborene ligand substitution and the coinage metal center, hinting at the potential for exploiting the properties of long-lived triplet excited states of metal diborene complexes in the future.

Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis.

Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.

Ultra-Long Lived Luminescent Triplet Excited States in Cyclic (Alkyl)(amino)carbene Complexes of Zn(II) Halides.

The high element abundance and d10 electron configuration make ZnII -based compounds attractive candidates for the development of novel photoactive molecules. Although a large library of purely fluorescent compounds exists, emission involving triplet excited states is a rare phenomenon for zinc complexes. We have investigated the photophysical and -chemical properties of a series of dimeric and monomeric ZnII halide complexes bearing a cyclic (alkyl)(amino)carbene (cAAC) as chromophore unit. Specifically, [(cAAC)XZn(µ-X)2 ZnX(cAAC)] (X=Cl (1), Br (2), I (3)) and [ZnX2 (cAAC)(NCMe)] (X=Br (4), I (5)) were isolated and fully characterized, showing intense visible light photoluminescence under UV irradiation at 297 K and fast photo-induced transformation. At 77 K, the compounds exhibit improved stability allowing to record ultra-long lifetimes in the millisecond regime. DFT/MRCI calculations confirm that the emission stems from 3 XCT/LEcAAC states and indicate the phototransformation to be related to asymmetric distortion of the complexes by cAAC ligand rotation. This study enhances our understanding of the excited state properties for future development and application of new classes of ZnII phosphorescent complexes.

Linear Carbene Pyridine Copper Complexes with Sterically Demanding N,N'-Bis(trityl)imidazolylidene: Syntheses, Molecular Structures, and Photophysical Properties.

The sterically demanding carbene ITr (N,N'-bis(triphenylmethyl)imidazolylidene) was used as a ligand for the preparation of luminescent copper(I) complexes of the type [(ITr)Cu(R-pyridine/R'-quinoline)]BF4 (R = H, 4-CN, 4-CHO, 2,6-NH2, and R' = 8-Cl, 6-Me). The selective formation of linear, bis(coordinated) complexes was observed for a series of pyridine and quinoline derivatives. Only in the case of 4-cyanopyridine a one-dimensional coordination polymer was formed, in which the cyano group of the cyanopyridine ligand additionally binds to another Cu atom in a bridging manner, thus leading to a trigonal planar coordination environment. In contrast, employing sterically less demanding monotrityl-substituted carbene 3, no (NHC)Cu-pyridine complexes could be prepared. Instead, a bis-carbene complex [(3)2Cu]PF6 was obtained which showed no luminescence. All linear pyridine/quinoline coordinated complexes show weak emission in solution but intense blue to orange luminescence doped with 10% in PMMA films and in the solid state either from triplet excited states with unusually long lifetimes of up to 4.8 ms or via TADF with high radiative rate constants of up to 1.7 × 105 s-1 at room temperature. Combined density functional theory and multireference configuration interaction calculations have been performed to rationalize the involved photophysics of these complexes. They reveal a high density of low-lying electronic states with mixed MLCT, LLCT, and LC character where the electronic structures of the absorbing and emitting state are not necessarily identical.

Ditopic Phosphide Oxide Group: A Rigidifying Lewis Base to Switch Luminescence and Reactivity of a Disilver Complex.

Heterodentate phosphines containing anionic organophosphorus groups remain virtually unexplored ligands in the coordination chemistry of coinage metals. A hybrid phosphine-phosphine oxide (o-Ph2PC6H4)2P(O)H (HP3O) readily forms the disilver complex [Ag2(P3O)2] (1) upon deprotonation of the (O)P-H fragment. Due to the electron-rich nature, the anionic phosphide oxide unit in 1 takes part in efficient intermolecular hydrogen bonding, which has an unusual and remarkably strong impact on the photoluminescence of 1, changing the emission from red (644 nm) to green-yellow (539 nm) in the solid. The basicity of the R2(O)P- group and its affinity for both inter- and intramolecular donor-acceptor interactions allow converting 1 into hydrohalogenated (2, 3) and boronated (4) derivatives, which reveal a gradual hypsochromic shift of luminescence, reaching the wavelength of 489 nm. Systematic variable-temperature analysis of the excited state properties suggests that thermally activated delayed fluorescence is involved in the emission process. The long-lived excited states for 1-4, the energy of which is largely regulated by means of the phosphide oxide unit, are potentially suitable for triplet energy transfer photocatalysis. With the highest T1 energy among 1-4, complex 4 demonstrates excellent photocatalytic activity in a [2+2] cycloaddition reaction, which has been realized for the first time for silver(I) compounds.

RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence.

Recent data suggest that therapy-resistant quiescent cancer stem cells (qCSCs) are the source of relapse in colon cancer. Here, using colon cancer patient-derived organoids and xenografts, we identify rare long-term label-retaining qCSCs that can re-enter the cell cycle to generate new tumors. RNA sequencing analyses demonstrated that these cells display the molecular hallmarks of quiescent tissue stem cells, including expression of p53 signaling genes, and are enriched for transcripts common to damage-induced quiescent revival stem cells of the regenerating intestine. In addition, we identify negative regulators of cell cycle, downstream of p53, that we show are indicators of poor prognosis and may be targeted for qCSC abolition in both p53 wild-type and mutant tumors. These data support the temporal inhibition of downstream targets of p53 signaling, in combination with standard-of-care treatments, for the elimination of qCSCs and prevention of relapse in colon cancer.