Dataset Information

KC-180-2 Exerts Anti-SCLC Effects via Dual Inhibition of Tubulin Polymerization and Src Signaling.

ABSTRACT: In this study, a series of N-benzyl-2-(5-phenylpyridin-2-yl) acetamide-based derivatives were successfully designed and synthesized as anti-cancer agents. KC-180-2 was screened as a potentially leading compound with dual mechanisms of action: Src signaling and tubulin polymerization inhibition. It efficiently suppressed the proliferation of five cancer cell lines (MDA-MB-231, H446, SKOV-3, HepG2, and HT29), with IC₅₀ values ranging from 5 to 188 nM, especially small-cell lung cancer (SCLC) cells (IC₅₀, 5 nM). Correspondingly, it exerted a significant therapeutic effect on the H446 small-cell lung cancer xenograft model, significantly reducing the volume of tumors without obvious toxicity. Mechanistically, this compound significantly inhibited the polymerization of purified tubulin in vitro, inducing G2/M cell cycle arrest and binding to the kinase catalytic domain of the Src protein, which reduced the phosphorylation of Src. Thus, KC-180-2 is a potential lead compound for the further development of a new anti-tumor drug against SCLC.

SUBMITTER: Peng J

PROVIDER: S-EPMC9476193 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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KC-180-2 Exerts Anti-SCLC Effects via Dual Inhibition of Tubulin Polymerization and Src Signaling.

Peng Jian J Zeng Yisheng Y Hu Xiaojun X Huang Sheng S Gao Xiaofang X Tian Dong D Tian Shuting S Qiu Lan L Liu Jin J Dong Renhan R Zhan Wei W Qin Chuanjun C Guang Bing B Yang Tai T

ACS omega 20220901 36

In this study, a series of <i>N</i>-benzyl-2-(5-phenylpyridin-2-yl) acetamide-based derivatives were successfully designed and synthesized as anti-cancer agents. KC-180-2 was screened as a potentially leading compound with dual mechanisms of action: Src signaling and tubulin polymerization inhibition. It efficiently suppressed the proliferation of five cancer cell lines (MDA-MB-231, H446, SKOV-3, HepG2, and HT29), with IC<sub>50</sub> values ranging from 5 to 188 nM, especially small-cell lung c ...[more]

PMID: 36120000

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Project description:The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of cancer cell growth with good therapeutic window with respect to normal cells. Among various non-planar tryptoline analogues prepared, N-(biphenyl-2-yl) tryptoline (BPT, 6) was identified as a potent inhibitor of cancer cell growth and free from DNA-binding properties owing to its non-planar structure. This compound was tested in over 60 protein kinase assays. It displayed inhibition of Cdk4-cyclin D1 enzyme in vitro far more potently than many other kinases including Cdk family members. Although it blocks growth of cancer cells deficient in the mitotic-spindle checkpoint at the G0/G1 phase of the cell cycle, the block occurs primarily at the G2/M phase. BPT inhibits tubulin polymerization in vitro and acts as an enhancer of tubulin depolymerization of paclitaxel-stabilized tubulin in live cells. Western blot analyses indicated that, in p53-positive cells, BPT upregulates the expression of p53, p21 and p27 proteins, whereas it downregulates the expression of cyclin B1 and Cdk1. BPT selectively kills SV40-transformed mouse embryonic hepatic cells and human fibroblasts rather than untransformed cells. BPT inhibited the growth of several human cancer cells with an IC50<1 μM. The pharmacokinetic study in BALB/c mice indicated good plasma exposure after intravenous administration. It was found to be efficacious at 1/10th the maximum-tolerated dose (1000 mg/kg) against human tumours derived from HCT-116 (colon) and NCI-H460 (lung) cells in SCID (severe-combined immunodeficient) mice models. BPT is a relatively better anticancer agent than fascaplysin with an unusual ability to block two overlapping yet crucial phases of the cell cycle, mitosis and G0/G1. Its ability to effectively halt tumour growth in human tumour-bearing mice would suggest that BPT has the potential to be a candidate for further clinical development.

Dataset Information

KC-180-2 Exerts Anti-SCLC Effects via Dual Inhibition of Tubulin Polymerization and Src Signaling.

Publications

KC-180-2 Exerts Anti-SCLC Effects via Dual Inhibition of Tubulin Polymerization and Src Signaling.

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