Lade Dhanaji M, Agazie Yehenew M
One Medical Center Drive, Department of Biochemistry and Molecular Medicine, School of Medicine, West Virginia University, P.O. Box 9142, Morgantown, West Virginia 26506, United States.
ACS Bio Med Chem Au. 2023 Jul 14;3(5):418-428. doi: 10.1021/acsbiomedchemau.3c00024. eCollection 2023 Oct 18.
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 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 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.
Src同源磷酸酪氨酸磷酸酶2（SHP2）是一种正在寻找靶向治疗方法的致癌蛋白。基于这一想法，我们之前报道了一种名为CNBDA的特异性活性位点抑制剂的研发，该抑制剂在抑制乳腺癌细胞的转化表型方面显示出有效性。为了提高疗效，我们对母体化合物进行了有限的修饰，并在细胞培养条件下测试了其效力。在这些修饰中，去除一个丁酸基团导致了一种名为CNBCA的化合物的产生，该化合物对SHP2酶活性的效力提高了5.7倍。此外，通过磷酸酶测定确定，CNBCA对SHP2的选择性优于对照蛋白酪氨酸磷酸酶（SHP1和PTP1B）。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对乳腺癌细胞的癌性特性有效。
