Machine learning-aided discovery of T790M-mutant EGFR inhibitor CDDO-Me effectively suppresses non-small cell lung cancer growth.
Epidermal growth factor receptor (EGFR) T790M mutation often occurs during long durational erlotinib treatment of non-small cell lung cancer (NSCLC) patients, leading to drug resistance and disease progression. Identification of new selective EGFR-T790M inhibitors has proven challenging through traditional screening platforms. With great advances in computer algorithms, machine learning improved the screening rates of molecules at full chemical spaces, and these molecules will present higher biological activity and targeting efficiency.
An integrated machine learning approach, integrated by Bayesian inference, was employed to screen a commercial dataset of 70,413 molecules, identifying candidates that selectively and efficiently bind with EGFR harboring T790M mutation. In vitro cellular assays and molecular dynamic simulations was used for validation. EGFR knockout cell line was generated for cross-validation. In vivo xenograft moues model was constructed to investigate the antitumor efficacy of CDDO-Me.
Our virtual screening and subsequent in vitro testing successfully identified CDDO-Me, an oleanolic acid derivative with anti-inflammatory activity, as a potent inhibitor of NSCLC cancer cells harboring the EGFR-T790M mutation. Cellular thermal shift assay and molecular dynamic simulation validated the selective binding of CDDO-Me to T790M-mutant EGFR. Further experimental results revealed that CDDO-Me induced cellular apoptosis and caused cell cycle arrest through inhibiting the PI3K-Akt-mTOR axis by directly targeting EGFR protein, cross-validated by sgEGFR silencing in H1975 cells. Additionally, CDDO-Me could dose-depended suppress the tumor growth in a H1975 xenograft mouse model.
CDDO-Me induced apoptosis and caused cell cycle arrest by inhibiting the PI3K-Akt-mTOR pathway, directly targeting the EGFR protein. In vivo studies in a H1975 xenograft mouse model demonstrated dose-dependent suppression of tumor growth. Our work highlights the application of machine learning-aided drug screening and provides a promising lead compound to conquer the drug resistance of NSCLC.
Zhou R
，Liu Z
，Wu T
，Pan X
，Li T
，Miao K
，Li Y
，Hu X
，Wu H
，Hemmings AM
，Jiang B
，Zhang Z
，Liu N
... -
《Cell Communication and Signaling》
Based on network pharmacology, molecular docking and experimental verification to reveal the mechanism of Andrographis paniculata against solar dermatitis.
Solar dermatitis (SD) is an acute, damaging inflammation of the skin caused by UV exposure, especially UVB. Therefore, the discovery of novel anti-SD therapeutic agents is crucial. Andrographis paniculata (AP) is a medicinal plant with a wide range of pharmacological effects. Increased evidence shows that AP has potential therapeutic effects on SD. However, the therapeutic mechanisms of AP against SD have not yet been completely elucidated, which is an unexplored field.
This study employed network pharmacology, molecular docking and experimental verification to ascertain the active constituents, possible targets, and biological pathways associated with AP in the treatment of SD.
AP-related active ingredients and their potential targets were screened from TCMSP and Swiss Target Prediction database, respectively. Potential therapeutic targets of SD were collected using the GeneCards, DrugBank and OMIM databases. Then, we established protein-protein interaction (PPI), compound-target-disease (D-C-T-D) through Cytoscape to identify the major components, core targets of AP against SD. Next, the GO and KEGG pathway was identified by the David database of AP in the treatment of SD. Molecular docking techniques were used to estimate the binding force between the components and the hub genes. In this paper, we used UVB-irradiated HaCaT keratinocytes as an in vitro model and established the dorsal skin of UVB-irradiated ICR mice as an in vivo model to explore the mechanism for further verification.
There were 24 active components and 63 related target genes in AP against SD. PPI analysis showed that AKT-1, TNF-α, IL6, MMP9, EGFR, and PTGS2 shared the highest centrality among all target genes. KEGG pathway analysis revealed that the PI3K-Akt signaling pathway may be central in the anti-SD system. The molecular docking results showed that the main active components of AP have strong binding affinity with hub genes. In vitro results showed that WG had a protective effect on UVB-intervened HaCat cells. Western blot analysis showed that WG intervention achieved anti-inflammation by reducing the phosphorylated expression of AKT, PI3K proteins in the PI3K-AKT signaling pathway and downregulating the expression of TNF-α, IL-6, EGFR. Furthermore, Histological analysis confirmed that administration of WG to ICR mice significantly ameliorated UVB-induced skin roughness, epidermal thickening, disturbed collagen fiber alignment and wrinkles. Meanwhile, immunohistochemistry showed that administration of WG to ICR mice significantly reduced UVB-induced expression of MMP9, MPO, F4/80 in the skin. These results provide new insights into the contribution of WG to the development of clinical treatment modalities for UVB-induced SD.
The crucial element in the fight against SD is WG, with the primary route being PI3K/Akt. The main components and hub genes had robust binding abilities. In vitro and vivo experiments showed that WG could inhibit the expression level of the hub genes by inhibiting the PI3K/Akt pathway. In summary, the information presented in this study indicates that WG might be utilised as a treatment for UVB-induced SD.
Deng Q
，Chen W
，Deng B
，Chen W
，Chen L
，Fan G
，Wu J
，Gao Y
，Chen X
... -
《-》
Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, which was overexpressed in non-small cell lung cancer (NSCLC) and essential for cell proliferation, migration and invasion. Recently, accumulating evidences indicated that ROR1 played a critical role in maintaining the balance between the Src survival pathway and the p38 apoptotic pathway. Hence, ROR1 was considered as an attractive therapeutic target for the development of anticancer drugs. However, only a few small molecule ROR1 inhibitors were reported until now. Herein, a series of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives were designed and synthesized via bioisosterism and simplification strategy guided by the lead compound 9a. MTT assay showed that compound 7h exhibited the best anti-cancer properties with IC50 values of 18.16, 8.11 and 3.5 μM against A549, PC9 and H1975 cells, respectively. Meanwhile, the selectivity index (SI) of compound 7h for H1975 cells was 22.86 compared to that of the lead compound 9a of 1.83, which is at least 12 fold higher than that of lead compound 9a, suggesting that 7h had a favorable safety profile. In addition, the molecular docking, CETSA and DARTS assays suggested that compound 7h might be a novel small molecule ROR1 inhibitor. More importantly, compound 7h significantly suppressed the migration and invasion of H1975 cells in vitro by blocking Src survival pathway and reactivating the p38 apoptotic pathway, and induced H1975 cell cycle arrest in G1 phase. Collectively, our work suggested that the ROR1 inhibitor 7h might be a novel drug candidate for NSCLC treatment.
Luo F
，Liu J
，Wang R
，Yang H
，Zhong T
，Su M
，Fan Y
... -
《-》
ResearchGate
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钛学术
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