Targeting SHP2 with an Active Site Inhibitor Blocks Signaling and Breast Cancer Cell Phenotypes

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-07-14 DOI:10.1021/acsbiomedchemau.3c00024
Dhanaji M. Lade,  and , Yehenew M. Agazie*, 
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Abstract

The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an oncogenic protein for which targeted therapies are being sought. In line with this idea, we have previously reported the development of a specific active site inhibitor named CNBDA that showed effectivity in suppressing the transformation phenotypes of breast cancer cells. To improve efficacy, we introduced limited modifications to the parent compound and tested potency in vitro and under cell culture conditions. Of these modifications, removal of one of the butyric acid groups led to the production of a compound named CNBCA, which showed a 5.7-fold better potency against the SHP2 enzyme activity in vitro. In addition, CNBCA showed better selectivity to SHP2 than the control PTPs (SHP1 and PTP1B) as determined by the phosphatase assay. Furthermore, CNBCA binds and inhibits enzyme activity of full-length SHP2 in cellular contexts, downregulates SHP2 mediated signaling, and suppresses breast cancer cell phenotypes, including cell proliferation, colony formation, and mammosphere growth. These findings show that targeting SHP2 with CNBCA is effective against the cancerous properties of breast cancer cells.

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用活性位点抑制剂靶向SHP2阻断信号传导和乳腺癌细胞表型
Src同源磷酸酪氨酸磷酸酶2(SHP2)是一种正在寻求靶向治疗的致癌蛋白。根据这一想法,我们之前报道了一种名为CNBDA的特异性活性位点抑制剂的开发,该抑制剂在抑制癌症细胞的转化表型方面表现出有效性。为了提高效力,我们对母体化合物进行了有限的修饰,并在体外和细胞培养条件下测试了效力。在这些修饰中,去除一个丁酸基团导致产生了一种名为CNBCA的化合物,该化合物在体外对SHP2酶活性的效力提高了5.7倍。此外,通过磷酸酶测定测定,CNBCA对SHP2表现出比对照PTP(SHP1和PTP1B)更好的选择性。此外,CNBCA在细胞环境中结合并抑制全长SHP2的酶活性,下调SHP2介导的信号传导,并抑制乳腺癌症细胞表型,包括细胞增殖、集落形成和乳腺球生长。这些发现表明,用CNBCA靶向SHP2对乳腺癌症细胞的癌性是有效的。
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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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