Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma

Ao Zhang; Zhen Guo; Jia-Xin Ren; Hongyu Chen; Wenzhuo Yang; Yang Zhou; Lin Pan; Zhuopeng Chen; Fei Ren; Youqi Chen; Menghan Zhang; Fei Peng; Wanting Chen; Xinhui Wang; Zhiyun Zhang; Hui Wu

doi:10.3389/fphar.2023.1162540

Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma

Front Pharmacol. 2023 Jul 19:14:1162540. doi: 10.3389/fphar.2023.1162540. eCollection 2023.

Authors

Ao Zhang¹, Zhen Guo², Jia-Xin Ren³, Hongyu Chen⁴, Wenzhuo Yang⁴, Yang Zhou⁵, Lin Pan⁵, Zhuopeng Chen⁴, Fei Ren⁵, Youqi Chen⁵, Menghan Zhang⁶, Fei Peng⁷, Wanting Chen⁵, Xinhui Wang⁸, Zhiyun Zhang⁹, Hui Wu¹⁰

Affiliations

¹ Department of Neurology, The First Hospital of Jilin University, Changchun, China.
² Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
³ Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China.
⁴ Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁵ Clinical College, Jilin University, Changchun, China.
⁶ Department of Clinical Laboratory, The Fifth Affiliated Hospital of Xinxiang Medical College, Xinxiang, China.
⁷ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX, United States.
⁸ Department of Hematology, The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, China.
⁹ Department of Plastic Surgery, The First Hospital of Jilin University, Changchun, China.
¹⁰ Department of Ophthalmology, First Hospital of Jilin University, Changchun, China.

Abstract

Introduction: The effect of the conventional treatment methods of glioblastoma (GBM) is poor and the prognosis of patients is poor. The expression of MCL-1 in GBM is significantly increased, which shows a high application value in targeted therapy. In this study, we predicted the prognosis of glioblastoma patients, and therefore constructed MCL-1 related prognostic signature (MPS) and the development of MCL-1 small molecule inhibitors. Methods: In this study, RNA-seq and clinical data of 168 GBM samples were obtained from the TCGA website, and immunological analysis, differential gene expression analysis and functional enrichment analysis were performed. Subsequently, MCL-1-associated prognostic signature (MPS) was constructed and validated by LASSO Cox analysis, and a nomogram was constructed to predict the prognosis of patients. Finally, the 17931 small molecules downloaded from the ZINC15 database were screened by LibDock, ADME, TOPKAT and CDOCKER modules and molecular dynamics simulation in Discovery Studio2019 software, and two safer and more effective small molecule inhibitors were finally selected. Results: Immunological analysis showed immunosuppression in the MCL1_H group, and treatment with immune checkpoint inhibitors had a positive effect. Differential expression gene analysis identified 449 differentially expressed genes. Build and validate MPS using LASSO Cox analysis. Use the TSHR HIST3H2A, ARGE OSMR, ARHGEF25 build risk score, proved that low risk group of patients prognosis is better. Univariate and multivariate analysis proved that risk could be used as an independent predictor of patient prognosis. Construct a nomogram to predict the survival probability of patients at 1,2,3 years. Using a series of computer-aided techniques, two more reasonable lead compounds ZINC000013374322 and ZINC000001090002 were virtually selected. These compounds have potential inhibitory effects on MCL-1 and provide a basis for the design and further development of MCL-1 specific small molecule inhibitors. Discussion: This study analyzed the effect of MCL-1 on the prognosis of glioblastoma patients from the perspective of immunology, constructed a new prognostic model to evaluate the survival rate of patients, and further screened 2 MCL-1 small molecule inhibitors, which provides new ideas for the treatment and prognosis of glioblastoma.

Keywords: MCL-1; glioblastoma (GBM); molecular docking; nomogram; virtual screening.