Structure-based design of new anticancer N3-Substituted quinazolin-4-ones as type I ATP-competitive inhibitors targeting the deep hydrophobic pocket of EGFR

Article

作者: Lotfy, Rahma ; Arafa, Reem K ; El-Mahdy, Ragaa Y ; Galal, Noha

Epidermal growth factor receptor (EGFR) is amongst the earliest targeted kinases by small-molecule inhibitors for the management of EGFR-positive cancer types. While a few inhibitors are granted FDA approval for clinical use, discovery of new inhibitors is still of merit to enhance ligand-binding stability and subsequent enzyme inhibition. Thus, a structure-based design approach was adopted to devise a new series of twenty-nine N3-substituted quinazolin-4-ones as type I ATP-competitive inhibitors targeting the deep hydrophobic pocket of EGFR. The most active compounds demonstrated potent IC₅₀s against MDA-MB-231 and HepG2 cancer cells being comparable to or better than the reference drugs erlotinib and lapatinib. IC₅₀s of 5f and 15a against MDA-MB-231 were 3.34 and 4.99, whilst those against HepG2 were 6.37 and 2.18 μM, respectively. Also, members of this series demonstrated selective cytotoxicity against cancer cell lines showing low toxicity on human skin fibroblast normal cells hFB-4. Both 5f and 15a also effectively inhibited EGFR with sub-micromolar respective IC₅₀s of 0.07 and 0.12 μM. The two derivatives halted the cell cycle progression of treated cancer cells and induced apoptosis as affirmed by flow cytometry along with RT-PCR-determined overexpression of the pro-apoptotic genes p53, Caspase 3, and Bax. Notably, docking and molecular dynamics simulations of members of this series of quinazolin-4-one derivatives showed that analogs with a short linker at the N3 position of the quinazoline ring exemplified by 5f bind to the active form of EGFR with their terminal aryl ring dwelling in the BPI pocket similar to erlotinib, while those with a longer linker represented by 15a bind to the inactive form in a comparable manner to lapatinib lodging the terminal phenyl in the BPII pocket.

2025-03-01·Acta Pharmacologica Sinica

A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2

Article

作者: Ding, Chun-Yong ; Xu, Lei-Yu ; Hu, Cheng-Hong ; Tang, Wei-Yang ; Jin, Bo ; Tang, Wei-yang ; Liao, Jing ; Liang, Guang ; Ning, Fang-Min ; Hu, Cheng-hong ; Jin, Tian-yang ; Jin, Tian-Yang ; Wei, Xiao-Hong ; Wei, Xiao-hong ; Chen, Yue ; Ning, Fang-min ; Zhang, Ao ; Zhang, Ling-Xi ; Wang, Zhe ; Xu, Lei-yu ; Wang, Yi ; Ding, Chun-yong ; Zhang, Ling-xi

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg^-1·d^-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg^-1·d^-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

2025-02-20·Chemistry – A European Journal

Synthesis of Thiazolidinedione‐ and Triazole‐Linked Organoselenocyanates and Evaluation of Anticancer Activities Against Breast Cancer with Mechanistic Investigations

Article

作者: Pal, Nikita ; Banerjee, Kaustav ; Sarkar, Shilpi ; Bhabak, Krishna P. ; Mandal, Tapas K.

AbstractOrganoselenocyanates are important classes of organoselenium compounds having potential pharmaceutical applications in cancer biology. In the present study, two different series of organoselenocyanates (15 a–15 c and 16 a–16 c) incorporating crucial heterocyclic pharmacophores such as 2,4‐thiazolidine‐1,3‐dione and 1,2,3‐triazole were rationally designed. The organoselenocyanates were synthesized using multi‐step organic synthesis and investigated for their anticancer activities against triple‐negative breast cancer cells. Based on the preliminary anti‐proliferative activities and the selectivity index towards cancer cells over the normal cells, 2,4‐thiazolidine‐1,3‐dione‐based selenocyanate 15 a was identified as the lead analogue for detailed investigations. In addition to the anti‐migratory activity, compound 15 a induced G1‐phase arrest of the cell cycle and led to early apoptosis. Further studies on the redox balance of MDA‐MB‐231 cells indicated the antioxidant nature of 15 a with the quenching of ROS level and upregulation of TrxR1 expression. Detailed mechanistic investigations with the expression levels of key‐cancer marker proteins revealed that the selenocyanate 15 a induced the activation of ERK pathway by upregulating p‐ERK expression with the subsequent downregulation of p‐Akt and c‐Myc levels leading to the inhibition of cellular proliferation. Therefore, the primary outcomes of the study would be valuable in the development of chemotherapeutic agents towards the treatment of triple‐negative breast cancer.

100 项与 15-a 相关的药物交易

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