Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor.

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).

Computational approach inspired advancements of solid-state electrolytes for lithium secondary batteries: from first-principles to machine learning.

The increasing demand for high-security, high-performance, and low-cost energy storage systems (EESs) driven by the adoption of renewable energy is gradually surpassing the capabilities of commercial lithium-ion batteries (LIBs). Solid-state electrolytes (SSEs), including inorganics, polymers, and composites, have emerged as promising candidates for next-generation all-solid-state batteries (ASSBs). ASSBs offer higher theoretical energy densities, improved safety, and extended cyclic stability, making them increasingly popular in academia and industry. However, the commercialization of ASSBs still faces significant challenges, such as unsatisfactory interfacial resistance and rapid dendrite growth. To overcome these problems, a thorough understanding of the complex chemical-electrochemical-mechanical interactions of SSE materials is essential. Recently, computational methods have played a vital role in revealing the fundamental mechanisms associated with SSEs and accelerating their development, ranging from atomistic first-principles calculations, molecular dynamic simulations, multiphysics modeling, to machine learning approaches. These methods enable the prediction of intrinsic properties and interfacial stability, investigation of material degradation, and exploration of topological design, among other factors. In this comprehensive review, we provide an overview of different numerical methods used in SSE research. We discuss the current state of knowledge in numerical auxiliary approaches, with a particular focus on machine learning-enabled methods, for the understanding of multiphysics-couplings of SSEs at various spatial and time scales. Additionally, we highlight insights and prospects for SSE advancements. This review serves as a valuable resource for researchers and industry professionals working with energy storage systems and computational modeling and offers perspectives on the future directions of SSE development.

Evaluation of omadacycline dosing regimens in Chinese using population pharmacokinetic-pharmacodynamic analysis.

PURPOSE: Omadacycline (PTK-0796) is a first-in-class aminomethylcycline for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible pathogens. We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of omadacycline, considering the impact of covariates, particularly ethnicity, on PK and determined the PK/PD cutoff values for dosing regimens. METHODS: Utilizing nonlinear mixed-effects modeling, we pooled data from 11 clinical trials for PopPK analysis. The first-order conditional estimation with interaction (FOCEI) method in NONMEM facilitated model parameter estimation. Employing a stepwise model selection strategy, with forward addition (P < 0.01) and backward deletion (P < 0.001), we assessed the potential impacts of covariates on omadacycline PK, including baseline age, body weight, sex, race, body mass index, body surface area, baseline albumin, creatine clearance, and formulation. After validating the model through various methods, the final PopPK model underwent Monte Carlo simulations to generate the PK profile for the Chinese population. This enabled AUC calculation and assessment of the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for various dosing regimens and bacterial strains. RESULTS: Omadacycline's PK can be adequately characterized by a three-compartment model. Body weight, sex, race, and drug formulation statistically influenced its PK. Asians and non-Asians exhibit similar exposure after intravenous infusion, but oral dosing results in much higher exposures than in non-Asians. Monte Carlo simulation indicates that IV-only or IV/PO sequential therapy regimens provide adequate attainment for all major pathogens causing ABSSSI and CABP. PK/PD cutoffs were generally above the MIC90 value of recent clinical isolates from China. CONCLUSIONS: In conclusion, the approved regimen for China achieved adequate target attainment for all pathogens typically associated with these infections. The higher oral exposure observed in Asians may enhance efficacy without affecting safety or tolerability.

A Minireview of the Solid-State Electrolytes for Zinc Batteries.

Aqueous zinc-ion batteries (ZIBs) have gained significant recognition as highly promising rechargeable batteries for the future due to their exceptional safety, low operating costs, and environmental advantages. Nevertheless, the widespread utilization of ZIBs for energy storage has been hindered by inherent challenges associated with aqueous electrolytes, including water decomposition reactions, evaporation, and liquid leakage. Fortunately, recent advances in solid-state electrolyte research have demonstrated great potential in resolving these challenges. Moreover, the flexibility and new chemistry of solid-state electrolytes offer further opportunities for their applications in wearable electronic devices and multifunctional settings. Nonetheless, despite the growing popularity of solid-state electrolyte-based-ZIBs in recent years, the development of solid-state electrolytes is still in its early stages. Bridging the substantial gap that exists is crucial before solid-state ZIBs become a practical reality. This review presents the advancements in various types of solid-state electrolytes for ZIBs, including film separators, inorganic additives, and organic polymers. Furthermore, it discusses the performance and impact of solid-state electrolytes. Finally, it outlines future directions for the development of solid-state ZIBs.

Agar-based hydrogel polymer electrolyte for high-performance zinc-ion batteries at all climatic temperatures.

Aqueous zinc-ion batteries (ZIBs) have received numerous attention because of their inherent safety and low cost. However, ZIBs are highly sensitive to temperature; the realization of full-temperature ZIBs is of great importance. In this study, an agar-based composite hydrogel polymer electrolyte (AG-HGPE) with the blend of agar and polyacrylamide (PAM) was prepared. It has a non-porous homogeneous structure, and shows various merits, e.g., strong liquid absorption rate, good mechanical properties, and large Zn2+ transference number. The corresponding Zn-symmetric cells possess reversible zinc stripping/plating phenomenon up to 500 h at a current density of 1 mA cm-2 and an areal capacity of 1 mAh cm-2. The Zn/AG-HGPE/V2O5 cells exhibit good rate performance and stable cyclic behaviors at -25°C, 25°C and 50°C, as well as excellent adaptability to the changes of ambient temperature. The research paves a new route for developing green energy storage devices running in wide temperature range.

RuO2-Incorporated Co3O4 Nanoneedles Grown on Carbon Cloth as Binder-Free Integrated Cathodes for Tuning Favorable Li2O2 Formation.

Developing ideal Li-O2 batteries (LOBs) requires the discharge product to have a large quantity, have large contact area with the cathode, and not passivate the porous surface after discharge, which put forward high requirement for the design of cathodes. Herein, combining the rational structural design and high activity catalyst selection, minor amounts of RuO2-incorporated Co3O4 nanoneedles grown on carbon cloth are successfully synthesized as binder-free integrated cathodes for LOBs. With this unique design, plenty of electron-ion-oxygen tri-phase reaction interface is created, the side reaction from carbon is isolated, and oxygen reduction reaction/oxygen evolution reaction (OER) kinetics are significantly facilitated. Upon discharge, film-like Li2O2 is observed growing on the needle surface first and eventually ball-like Li2O2 particles form at each tip of the needle. The cathode surface remains porous after discharge, which is beneficial to the OER and is rare in the previous reports. The battery exhibits a high specific discharge capacity (7.64 mAh cm-2) and a long lifespan (500 h at 0.1 mA cm-2). Even with a high current of 0.3 mA cm-2, the battery achieves a cycling life of 200 h. In addition, punch-type LOBs are fabricated and successfully operated, suggesting that the cathode material can be utilized in ultralight, flexible electronic devices.

Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

Versatile Asymmetric Separator with Dendrite-Free Alloy Anode Enables High-Performance Li-S Batteries.

Lithium-sulfur batteries (LSBs) with extremely-high theoretical energy density (2600 Wh kg-1 ) are deemed to be the most likely energy storage system to be commercialized. However, the polysulfides shuttling and lithium (Li) metal anode failure in LSBs limit its further commercialization. Herein, a versatile asymmetric separator and a Li-rich lithium-magnesium (Li-Mg) alloy anode are applied in LSBs. The asymmetric separator is consisted of lithiated-sulfonated porous organic polymer (SPOP-Li) and Li6.75 La3 Zr1.75 Nb0.25 O12 (LLZNO) layers toward the cathode and anode, respectively. SPOP-Li serves as a polysulfides barrier and Li-ion conductor, while the LLZNO functions as an "ion redistributor". Combining with a stable Li-Mg alloy anode, the symmetric cell achieves 5300 h of Li stripping/plating and the modified LSBs exhibit a long lifespan with an ultralow fading rate of 0.03% per cycle for over 1000 cycles at 5 C. Impressively, even under a high-sulfur-loading (6.1 mg cm-2 ), an area capacity of 4.34 mAh cm-2 after 100 cycles can still be maintained, demonstrating high potential for practical application.

Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent.

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

Pharmacokinetics, Safety and Pharmacokinetics/Pharmacodynamics Analysis of Omadacycline in Chinese Healthy Subjects.

Objective: Omadacycline is a new type of aminomethylcycline antibiotic, having a broad antibacterial spectrum. But the pharmacokinetic characteristics and safety profile of the Chinese population remain unknown. It is also unclear whether the US-approved treatment regimen is applicable for the Chinese population. Methods: In a randomized, double-blinded, placebo-controlled dose-escalated trial, the pharmacokinetics of omadacycline was evaluated by a non-compartmental and compartmental model. Monte Carlo simulations were performed using the pharmacokinetic data from the Chinese population to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the US FDA-approved dose regimen. Results: The three-compartment model successfully described the rapid distribution and slow elimination of omadacycline after the intravenous infusion (i.v.). The double-peak concentration-time curve of the oral absorption (p.o.) was explained by the two-compartment model with two absorption compartments. The steady-state AUC of 100 mg omadacycline i.v. and 300 mg omadacycline p. o. were 12.1 and 19.4 mg h/L, respectively. Pharmacokinetics/pharmacodynamics (PK/PD) analysis showed that the omadacycline dosing regimen with a loading dose (200 mg i.v. q24 h, 100 mg i.v. q12 h, 450 mg p. o. q24 h × 2 days or 300 mg p. o. q12 h) and maintenance dose (100 mg i.v. q24 h or 300 mg p. o. q24 h) could cover the main pathogens of the indications acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP): Staphylococcus aureus and Streptococcus pneumoniae. Also, omadacycline had showed a good safety profile in the Chinese population. Conclusions: With the evidence provided, omadacycline could be a novel treatment option to Chinese patients with ABSSSI and CABP.

Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD).

We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).

Formation/Decomposition of Li2O2 Induced by Porous NiCeOx Nanorod Catalysts in Aprotic Lithium-Oxygen Batteries.

To realize the utilization of high-performance lithium-oxygen batteries (LOBs), a rational-designed cathode structure and efficient catalytic materials are necessary. However, side products accumulated during battery cycling seriously affects the performance. Designing a cathode catalyst that could simultaneously facilitate the catalytic efficiency of the main reaction and inhibit the side reactions will make great sense. Herein, NiCeOx was proposed for the first time as a bifunctional cathode catalyst material for LOBs. The combined action of NiO and CeO2 components was expected to facilitate the decomposition of byproducts (e.g., Li2CO3), increase the oxygen vacancy content in CeO2, and enhance the adsorption of oxygen and superoxide. NiCeOx nanorods (NiCeOx PNR) were prepared using electrospinning method. It showed a hollow and porous nanorod (PNR)-like structure, which provided a large number of catalytic active sites and facilitated the transport of reactants and the deposition of discharge products. As a result, a high specific discharge capacity (2175.9 mAh g-1) and a long lifespan (67 cycles at 100 mA g-1 with a limited capacity of 500 mAh g-1) were obtained.

Boosting Polysulfide Catalytic Conversion and Facilitating Li+ Transportation by Ion-Selective COFs Composite Nanowire for LiS Batteries.

The large-scale application of lithium-sulfur batteries (LSBs) has been impeded by the shuttle effect of lithium-polysulfides (LiPSs) and sluggish redox kinetics since which lead to irreversible capacity decay and low sulfur utilization. Herein, a hierarchical interlayer constructed by boroxine covalent organic frameworks (COFs) with high Li+ conductivity is fabricated via an in situ polymerization method on carbon nanotubes (CNTs) (C@COF). The as-prepared interlayer delivers a high Li+ ionic conductivity (1.85 mS cm-1 ) and Li+ transference number (0.78), which not only acts as a physical barrier, but also a bidirectional catalyst for LiPSs redox process owing to the abundant heterointerfaces between the inner conductive CNTs and the outer COFs. After coupling such a catalytic interlayer with sulfur cathode, the LSBs exhibit a low decay rate of 0.07% per cycle over 500 cycles at 1 C, and long cycle life at 3 C (over 1000 cycles). More importantly, a remarkable areal capacity of around 4.69 mAh cm-2 can still be maintained after 50 cycles even under a high sulfur loading condition (6.8 mg cm-2 ). This work paves a new way for the design of the interlayer with bidirectional catalytic behavior in LSBs.

Low-Cost Zinc-Alginate-Based Hydrogel-Polymer Electrolytes for Dendrite-Free Zinc-Ion Batteries with High Performances and Prolonged Lifetimes.

Aqueous zinc-ion batteries (ZIBs) represent an attractive choice for energy storage. However, ZIBs suffer from dendrite growth and an irreversible consumption of Zn metal, leading to capacity degradation and a low lifetime. In this work, a zinc-alginate (ZA) hydrogel-polymer electrolyte (HGPE) with a non-porous structure was prepared via the solution-casting method and ion displacement reaction. The resulting ZA-based HGPE exhibits a high ionic conductivity (1.24 mS cm-1 at room temperature), excellent mechanical properties (28 MPa), good thermal and electrochemical stability, and an outstanding zinc ion transference number (0.59). The ZA-based HGPE with dense structure is proven to benefit the prevention of the uneven distribution of ion current and facilitates the reduction of excessive interfacial resistance within the battery. In addition, it greatly promotes the uniform deposition of zinc ions on the electrode, thereby inhibiting the growth of zinc dendrites. The corresponding zinc symmetric battery with ZA-based HGPE can be cycled stably for 800 h at a current density of 1 mA cm-2, demonstrating the stable and reversible zinc plating/stripping behaviors on the electrode surfaces. Furthermore, the quasi-solid-state ZIB with zinc, ZA-based HGPE, and Ca0.24V2O5 (CVO) as the anode, electrolyte, and cathode materials, respectively, show a stable cyclic performance for 600 cycles at a large current density of 3 C (1 C = 400 mA g-1), in which the capacity retention rate is 88.7%. This research provides a new strategy for promoting the application of the aqueous ZIBs with high performance and environmental benignity.

Porous Co2VO4 Nanodisk as a High-Energy and Fast-Charging Anode for Lithium-Ion Batteries.

High-energy-density lithium-ion batteries (LIBs) that can be safely fast-charged are desirable for electric vehicles. However, sub-optimal lithiation potential and low capacity of commonly used LIBs anode cause safety issues and low energy density. Here we hypothesize that a cobalt vanadate oxide, Co2VO4, can be attractive anode material for fast-charging LIBs due to its high capacity (~ 1000 mAh g-1) and safe lithiation potential (~ 0.65 V vs. Li+/Li). The Li+ diffusion coefficient of Co2VO4 is evaluated by theoretical calculation to be as high as 3.15 × 10-10 cm2 s-1, proving Co2VO4 a promising anode in fast-charging LIBs. A hexagonal porous Co2VO4 nanodisk (PCVO ND) structure is designed accordingly, featuring a high specific surface area of 74.57 m2 g-1 and numerous pores with a pore size of 14 nm. This unique structure succeeds in enhancing Li+ and electron transfer, leading to superior fast-charging performance than current commercial anodes. As a result, the PCVO ND shows a high initial reversible capacity of 911.0 mAh g-1 at 0.4 C, excellent fast-charging capacity (344.3 mAh g-1 at 10 C for 1000 cycles), outstanding long-term cycling stability (only 0.024% capacity loss per cycle at 10 C for 1000 cycles), confirming the commercial feasibility of PCVO ND in fast-charging LIBs.

Nonporous Gel Electrolytes Enable Long Cycling at High Current Density for Lithium-Metal Anodes.

Lithium-metal anodes with high theoretical capacity and ultralow redox potential are regarded as a "holy grail" of the next-generation energy-storage industry. Nevertheless, Li inevitably reacts with conventional liquid electrolytes, resulting in uneven electrodeposition, unstable solid electrolyte interphase, and Li dendrite formation that all together lead to a decrease in active lithium, poor battery performance, and catastrophic safety hazards. Here, we report a unique nonporous gel polymer electrolyte (NP-GPE) with a uniform and dense structure, exhibiting an excellent combination of mechanical strength, thermal stability, and high ionic conductivity. The nonporous structure contributed to a uniform distribution of lithium ions for dendrite-free lithium deposition, and Li/NP-GPE/Li symmetric cells can maintain an extremely low and stable polarization after cycling at a high current density of 10 mA cm-2. This work provides an insight that the NP-GPE can be considered as a candidate for practical applications for lithium-metal anodes.

Co3O4@NiCo2O4 double-shelled nanocages with hierarchical hollow structure and oxygen vacancies as efficient bifunctional electrocatalysts for rechargeable Zn-air batteries.

Highly efficient bifunctional oxygen electrocatalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are crucially important for the rechargeable Zn-air battery, a potential power source for applications in electric vehicles and grid-scale stationary storage systems. Herein, Co3O4@NiCo2O4 double-shelled nanocages (Co3O4@NiCo2O4 DSNCs) with hierarchical hollow structure and oxygen vacancies were designed and synthesized via annealing metal-organic frameworks. Co3O4@NiCo2O4 DSNCs with large specific surface area and three-dimensional interconnected mesopores and cavity not only provide more reaction sites, but also offer an efficient transport environment for reactants. Moreover, oxygen vacancies on the surfaces improve the capture of oxygen species to enhance the reactivity of the catalyst. Consequently, Co3O4@NiCo2O4 DSNCs displayed excellent bifunctional electrocatalytic performance, with a positive half-wave potential of 0.81 V (vs. reversible hydrogen electrode, RHE) for ORR (approaching the potential of commercial Pt/C catalyst) and a low potential of 1.65 V at 10 mA cm-2 for OER (exceeding Pt/C). In a practical demonstration, the Zn-air battery using Co3O4@NiCo2O4 DSNCs as the cathode delivered a satisfactory power density of 102.1 mW cm-2, comparable to the Zn-air battery with a Pt/C cathode, and exhibited much longer cycling stability.

Two-dimensional graphitic carbon nitride/N-doped carbon with a direct Z-scheme heterojunction for photocatalytic generation of hydrogen.

Photocatalysts with a direct Z-scheme heterojunction are promising by virtue of the effectively enhanced separation of charge carriers, high retention of redox ability and the absence of backward photocatalytic reactions. Their activity depends on band alignment and interfacial configurations between two semiconductors for charge carrier kinetics and the effective active sites for photochemical reactions. Herein, a two-dimensional (2D) graphitic carbon nitride/N-doped carbon (C3N4/NC) photocatalyst is synthesized by a gas template (NH4Cl)-assisted thermal condensation method. C3N4/NC has the synthetic merits of a direct Z-scheme heterojunction, 2D-2D interfacial contact, and enhanced specific surface area to improve charge separation kinetics and provide abundant active sites for photochemical reaction. It exhibits an over 46-fold increase of the photocatalytic hydrogen production rate compared to bulk C3N4 under visible light illumination. This work demonstrates the great potential of 2D Z-scheme heterojunctions for photocatalysis and will inspire more related work in the future.

2,3-Dimethoxy-2,3-dimethyl-1,4-dioxane as a useful precursor to 2,3-dimethylene-1,4-dioxane for [4+2] cycloaddition reaction.

2,3-Dimethoxy-2,3-dimethyl-1,4-dioxane readily prepared from biacetyl serves as a stable precursor to 2,3-dimethylene-1,4-dioxane which undergoes a [4+2] cycloaddition reaction with dienophiles to give functionalized cyclohexene derivatives. The cycloaddition adducts obtained by the present procedure are transformed into potentially useful intermediates for biologically important materials.

N-Alkylation/aldol reaction of α-aldimino thioesters: a facile three-component coupling reaction.

Theoretical calculation of the reactivity of α-imino thioesters indicates that they are very reactive substrates for Umpolung N-alkylation. In fact, treatment of α-aldimino thioesters with dialkylzinc reagents in the presence of aldehydes or imines gives three-component coupling products in good yields.