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Background and Purpose: Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer., Experimental Approach: NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses., Key Results: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC 50 , 3.51 μM vs. 35.45 μM) and DU145 (IC 50 , 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3., Conclusion and Implications: NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy., (© 2024 British Pharmacological Society.)

Based on the scaffold hybridization strategy, twenty-four indole-guanidines were designed and synthesized. Subsequently, anti-proliferative activity against various cancer cells indicated that most of these hybrids exhibited moderate to high anti-proliferative activity, especially for human hepatoma cell lines. Selectivity investigation showed that these hybrids showed the best selectivity for SMMC-7721 subtype in human hepatoma cells. Particularly, (E)-3-((2-(N-pentylcarbamimidoyl)hydrazono)methyl)-1H-indol-5-yl 4-methylbenzoate (19) and (E)-3-((2-(N-pentylcarbamimidoyl)hydrazono)methyl)-1H-indol-5-yl 4-methoxybenzoate (22) exhibited potent inhibition against SMMC-7721 cells with IC 50 values of 0.057 μM and 0.042 μM, respectively, far outperforming that of Sorafenib. Meanwhile, hybrids 19 and 22 exhibited no significant cytotoxicity against normal cells such as HEK293 cells and HEK293T cells. Moreover, further investigations indicated that hybrid 22 effectively induced apoptosis, arrested the cell cycle at S phase, and selectively down regulated expression of p-STAT3, JAK2 and BRAF in SMMC-7721 cells in a dose-dependent manner. Molecular docking indicated that hybrid 22 exhibited high affinity with STAT3 and BRAF. In summary, hybrid 22 was developed as a potential and effective anti-hepatoma candidate, which was worthy of further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a 'triplet' inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Recently approved multi-target inhibitors of receptor tyrosine kinases (RTKs) have significantly improved the clinical treatment of cancers. A series of N,N'-diarylureas incorporated with aromatic heterocycle have been designed, synthesized and evaluated as novel multi-target RTK inhibitors. The preliminary biological evaluation indicated that several compounds exhibited comparable potency with Sorafenib. Among them, compound 6f was identified as the most potent multikinase inhibitor of EGFR, KDR and FGFR1 with IC50 values of 14.83nM, 21.57nM, and 28.23nM, respectively. These compounds expanded the structural diversity of diarylureas as RTK inhibitors. The results demonstrated that compound 6f could be served as novel lead compound for further development of multi-target RTK inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of N,N'-dibenzoylpiperazine derivatives incorporated with 1H-indazol-3-amine have been designed, synthesized and evaluated as novel Bcr-Abl inhibitors. Several title compounds exhibited potent inhibitory activity against Bcr-Abl wild type as well as T315I mutant. Two compounds, 11a and 12c, strongly suppressed the activity of native and mutant Bcr-Abl. In particular, 11a exhibited comparable potency with that of Imatinib. It potently inhibited both Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 values of 0.014 μM and 0.45 μM, respectively. Furthermore, compound 11a also inhibited the proliferation of K562 leukemia cancer cells. Therefore, it could serve as promising lead compound for further optimization of Bcr-Abl(WT) and Bcr-Abl(T315I) inhibitors., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Antiangiogenic therapy might represent a new promising anticancer therapeutic strategy. Taspine can significantly inhibit cell proliferation of human umbilical vein endothelial cells (HUVECs) induced by vascular endothelial growth factor-165, which is crucial for angiogenesis. In this study, a series of novel taspine derivatives were synthesized and screened for in vitro anticancer and antiangiogenesis activities. The majority of the derivatives demonstrated a moderate degree of cytotoxicity against human cancer cell lines. One of them (14) exhibited much better antiproliferative activity against CACO-2 (IC(50)=52.5microM) and ECV304 (IC(50)=2.67microM) cells than taspine did. Some of them were also effective in antiproliferative assays against HUVECs. The in silico estimate of solubility of title compounds were higher than that of taspine., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

A series of 2-phenoxy-N-phenylacetamides were designed and synthesized with a view to develop novel anticancer agents. All compounds were prepared with varied substitutions in the phenyl ring of aniline and evaluated for their anticancer activity. The majority of them displayed a moderate degree of cytotoxicity against several human cancer cell lines. Six compounds displayed potent cell growth inhibitory activity with IC values below 20 μM. Two compounds ( TC-5 and TC-14) exhibited the most pronounced antiproliferative activity equivalent to or higher than that of positive control. The structure - activity relationship of these anticancer agents has been reviewed. The results indicate that incorporation of halogen into the benzene ring is beneficial for anticancer activity. [ABSTRACT FROM AUTHOR]

VEGFR-2 plays an essential role in angiogenesis and is a central target for anticancer drug discovery. In order to develop novel VEGFR-2 inhibitors, we designed and synthesized 33 biphenyl amides based on our previously reported lead compound. The biological results indicated that four compounds ( 18b , 20e , 20h and 20j ) are potent VEGFR-2 inhibitors which are comparable to positive control. Compound 18b displayed the most potent VEGFR-2 inhibition with IC 50 value of 2.02 nM. Moreover, it exhibited promising antiproliferative activity against MCF-7 and SMMC-7721 cells with IC 50 values of 1.47 μM and 5.98 μM, respectively. Molecular docking and 3D-QSAR studies were also carried out. The results indicated that these biphenyl amides could serve as promising leads for further optimization as novel VEGFR-2 inhibitors. [ABSTRACT FROM AUTHOR]