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CDK8 is a member of the CDK family in which belongs to the serine/threonine protein kinase. It binds with cyclin C to regulate the transcription. By modulation of various gene expression programs, CDK8 associated with the mediator complex to sustain proliferation and viability of cancer cells. CDK8 has been identified as an important factor in cancer occurrence and development. It also involves in the regulation of cancer cell stress response to radiotherapy and chemotherapy, assists tumor cell invasion, metastasis and drug resistance. Therefore inhibition of CDK8 is regarded as a promising target for cancer therapy. ABM-3249 was discovered as a potent and selective CDK8 inhibitor with a novel chemical structure. It inhibited CDK8 kinase activity in biochemical assay and cellular binding assay, with IC50 values of 1.4 nM and 19nM respectively. ABM-3249 displayed good kinase selectivity: <50% inhibition on all other CDK family members at 1uM. Consistently, ABM-3249 reduced STAT1-S727 phosphorylation with an IC50 of less than 100nM. ABM-3249 showed good ADME properties with high oral bioavailability (~90%) in rodents. In efficacy studies, ABM-3249 exhibited excellent anti-tumor activities in multiple in vivo models. In an AML MV4-11 xenograft model at 25mpk oral dosing ABM-3249 achieved complete remission in all mice within 17 days and no tumor recurrence within one month after drug withdrawal. ABM-3249 showed good efficacies as a single agent, as well as a synergetic effect with anti-PD1 combination in a murine colon cancer MC38 model. It also showed an efficacy in a murine colon cancer B16F10 metastasis model. In addition, ABM-3249 displayed a good safety margin in a preliminary tox screen in rodents. Citation Format: Chen Chen, Charles Huang, Min Xu, Xiuquan Chen, Xiaobing Lv, Chen Yang, Lanjiao Zhao, YouQin Chen, Jizhi Li, Li Zhao. A potent and selective CDK8 inhibitor ABM-3249 with excellent efficacies in multiple in vivo cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5982.

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This paper studies the express train transportation organization to ensure that the cargo can be delivered in the shortest time. Based on this, this paper makes the following research: By comparing the characteristics of express cargo and the characteristics of its transportation, the time value of express cargo is studied. This paper analyzes the transportation organization of the express train, introduces the organization of the express train, and divides it into direct trains and transit trains to analyze the transportation organization process. Then, the model of the express train transfer node selection model is established. The model is based on the minimum cost of the train and the sum of the unit mileage cost and the time cost. The conditions for the delivery of various cargo, transportation capacity and traffic flow are constrained. The model and the solution ideas are proposed. The above model is verified by constructing a virtual network and formulating reasonable data. Finally, the stop nodes of each express train are obtained, and the correctness of the model is verified.