Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.

It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC50 = 0.02 ± 0.01 µM, MV4-11 GC50 = 0.03 ± 0.01 µM). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

Theoretical analysis and experiment of pressure distribution and pressure gradient of shield screw conveyor: Taking sandy soil as an example.

The pressure distribution and pressure gradient characteristics of shield screw conveyor directly affect its normal function. Taking the conditioned soil microelements in the spiral tube as the research object, the pressure field distribution and pressure gradient theoretical calculation model of the shield screw machine were established based on the stress analysis and the mechanical equilibrium conditions at steady state and the influence parameters were analyzed. The correctness and validity of the proposed calculation model are verified by the experimental results of the indoor model machine. Under the condition that the conditioned soil is the plastic fluid paste, the conclusion that the pressure field and pressure gradient of the shield screw machine decrease linearly along the direction of the screw axis is also obtained.