1001020-08-1Relevant articles and documents
Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer
Yao, Dahong,Huang, Jian,Wang, Jinhui,He, Zhendan,Zhang, Jin
, p. 1524 - 1538 (2020)
The overexpression of P21-activated kinase 1 (PAK1) is associated with poor prognosis in several cancers, which has emerged as a promising drug targets. Based on high-throughput virtual screening strategy, tetrahydrothieno [2,3-c]pyridine scaffold was identified as an initial lead for targeting PAK1. Herein we reported our structure-based optimisation strategy to discover a potent PAK1 inhibitor (7j) which displayed potent PAK1 inhibition and antiproliferatory activity in MDA-MB-231 cells. 7j induced obviously G2/M cell cycle arrest via PAK1-cdc25c-cdc2 pathway, and also inhibited MAPK-ERK and MAPK-JNK cascade to induce MDA-MB-231 cell death. Together, these results provided a novel chemical scaffold as PAK1 inhibitor for breast cancer treatment.
Synthesis and application of novel anti-tumor active compound
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Paragraph 0012; 0013, (2020/04/06)
The invention relates to synthesis and application of a novel anti-tumor active compound, and belongs to the technical field of anti-tumor pharmacy. The technical problem to be solved by the inventionis to provide a compound which is used as an anti-colorectal cancer cell but not limited to a colorectal cancer cell. The compound comprises a compound as shown in the specification or a pharmaceutically acceptable salt thereof. According to the compound or the pharmaceutically acceptable salt thereof, the application is the application of the novel compound in preparation of anti-cancer drugs, and the compound has certain inhibitory activity on tumor cells, especially HCT116 and Hep-G2, so that a new choice is provided for treatment of related tumors. The compound disclosed by the inventionis simple in structure and good in activity, can be used as a leading compound of an anti-cancer drug, and has a good application prospect. The formula I is shown in the specification.
Discovery of Thieno[2,3- d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells
Pan, Zhaoping,Li, Xiang,Wang, Yujia,Jiang, Qinglin,Jiang, Li,Zhang, Min,Zhang, Nan,Wu, Fengbo,Liu, Bo,He, Gu
, p. 3678 - 3700 (2020/04/30)
Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.
