Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo[1,2-a]quinoxalin-4(5H)-one and imidazo[1,2-a]quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.

Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK).

Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.

Enhanced cyclability of Li-O2 batteries with cathodes of Ir and MnO2 supported on well-defined TiN arrays.

The cycling stability of Li-O2 batteries has been impeded by the lack of high-efficiency, and durable oxygen cathodes for the oxygen-reduction reaction (ORR) and the oxygen-evolution reaction (OER). Herein we report a novel TiN nanorod array-based cathode, which was firstly prepared by growing a TiN nanorod array on carbon paper (CP), and then followed by depositing MnO2 ultrathin sheets or Ir nanoparticles on the TiN nanorods to form well-ordered, three-dimensional (3D), and free-standing structured cathodes: TiN@MnO2/CP and TiN@Ir/CP. Both cathodes exhibited good specific capacity and excellent cycling stability. Their specific discharge capacities were up to 2637 and 2530 mA h g-1, respectively. After 200 cycles for 2000 h at a current density of 100 mA g-1, no obvious decays were observed for TiN@MnO2/CP and TiN@Ir/CP cathodes, while significant decreases were observed after the 80th and 30th cycles for the Pt/C and TiN/CP cathodes, respectively. Such high performance can be ascribed to the 3D array structure with enough microspace and high surface area, which facilitated the high dispersion of active components and prevented the formation of large/irreversible Li2O2.