Rational design of small molecule RHOA inhibitors for gastric cancer

Kim, Jinhee; Park, Sungjin; Lim, Seung Mook; Eom, Hyo Jin; Balch, Curt; Lee, Jinhyuk; Kim, Gi Jin; Jeong, Jeong‐Won; Nam, Seungyoon; Kim, Yon Hui

doi:10.1038/s41397-020-0153-6

Cited by 9 publications

(15 citation statements)

References 39 publications

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“…The anti-cancer activity of this combination, along with the fact that GPCR-signaling related genes comprised seven out of the top one hundred drop-out candidates, underscores the importance of GPCR signaling components as targets in cancer drug-combination therapy 93 – 95 . Particularly, our findings point to GTPase signaling targets as highly relevant for achieving synthetic vulnerability in SRC-inhibited cancer cells 96 , as supported by previously published studies 97 – 99 . Interestingly, we found that RhoA inhibition was predominantly effective in LNCaP prostate cancer cells, which aligns with the previously demonstrated importance of RhoA in this type of malignancy and suggests combined co-inhibition of RhoA and SRCs as a potential treatment for prostate cancer 100 , 101 .…”

Section: Discussionsupporting

confidence: 85%

A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells

Gilad

Eliaz

et al. 2021

Commun Biol

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Steroid receptor coactivator 3 (SRC-3/NCoA3/AIB1), is a key regulator of gene transcription and it plays a central role in breast cancer (BC) tumorigenesis, making it a potential therapeutic target. Beyond its function as an important regulator of estrogen receptor transcriptional activity, SRC-3 also functions as a coactivator for a wide range of other transcription factors, suggesting SRC-3 inhibition can be beneficial in hormone-independent cancers as well. The recent discovery of a potent SRC-3 small molecule inhibitor, SI-2, enabled the further development of additional related compounds. SI-12 is an improved version of SI-2 that like SI-2 has anti-proliferative activity in various cancer types, including BC. Here, we sought to identify gene targets, that when inhibited in the presence of SI-12, would lead to enhanced BC cell cytotoxicity. We performed a genome-scale CRISPR-Cas9 screen in MCF-7 BC cells under conditions of pharmacological pressure with SI-12. A parallel screen was performed with an ER inhibitor, fulvestrant, to shed light on both common and distinct activities between SRC-3 and ERα inhibition. Bearing in mind the key role of SRC-3 in tumorigenesis of other types of cancer, we extended our study by validating potential hits identified from the MCF-7 screen in other cancer cell lines.

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Section: Discussionsupporting

confidence: 85%

A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells

Gilad

Eliaz

et al. 2021

Commun Biol

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“…To determine whether Myc-target genes and G2/M-checkpoint related genes were suppressed due to the RHOA inhibition, we inspected publicly available independent datasets. For validating the expression levels of RHOA , Myc-target genes, and G2/M-checkpoint-related genes, we re-visited and inspected the transcriptome data (GEO accession: GSE135068) [ 10 ] from our previous study of other RHOA inhibitors (JK-136 and -139). We found that, upon RHOA inhibition by JK-136 and -139, most of the expression levels of RHOA and DEGs related to Myc targets and G2/M checkpoint (depicted in Figure 4 b) were consistently decreased ( Figure S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…We performed DEG analysis using a microarray of GC cells treated with JK-206/-312 versus DMSO. For GC cell samples treated with DMSO, we used three samples (GEO accession numbers: GSM3984792, GSM3984796, and GSM3984800) from our previous dataset (GEO accession number: GSE135068) [ 10 ].…”

Section: Methodsmentioning

confidence: 99%

“…To validate the mRNA expression patterns of DEGs in publicly available independent datasets, we inspected the expression levels of RHOA and DEGs using publicly available transcriptome datasets, GSE135068 [ 10 ] and the expression level dataset of the Cancer Cell Line Encyclopedia (CCLE) [ 16 ], GSE110237 [ 17 ], and GSE83913 [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…We previously found that among JK-122–125, JK-122 showed superior suppression of cell viability [ 8 ]. In a follow-up study, we identified that JK-136 and JK-139 inhibited cell migration through the lead optimization of JK-122 [ 10 ]. Despite the potential of RHOA as a therapeutic target for GC, small-molecule RHOA inhibitors are underexplored [ 8 , 10 ] and the anticancer mechanism of RHOA inhibitors remain to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer

Beak

Park

Kim

et al. 2022

Cancers

Self Cite

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Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.

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Screening of small molecule inhibitors against RhoA protein from Alisma using an online detection system

Yan

Wang

Chen

2022

Journal of Chromatography A

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Rational design of small molecule RHOA inhibitors for gastric cancer

Cited by 9 publications

References 39 publications

A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells

A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells

Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer

Screening of small molecule inhibitors against RhoA protein from Alisma using an online detection system

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