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A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.

ABSTRACT: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ?70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.

SUBMITTER: Shen X

PROVIDER: S-EPMC6873189 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.

Shen Xiaofei X Zhao Lin L Chen Peihao P Gong Yanqiu Y Liu Dingdong D Zhang Xia X Dai Lunzhi L Sun Qingxiang Q Lou Jizhong J Jin Zhong Z Zhang Baohua B Niu Dawen D Chen Ceshi C Qi Xiangbing X Jia Da D

The Journal of biological chemistry 20191008 46

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an <i>ent</i>-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown an ...[more]

PMID: 31594861

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Project description:BackgroundTo optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1.Methodology and principal findingsIn vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤ 10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity.ConclusionsNSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.

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A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.

Publications

A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.

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