Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent.

Nannan Wu, Guangyu Lian, Jingyi Sheng, Dan Wu, Xiyong Yu, Huiyao Lan, Wenhui Hu, Zhongjin Yang

Bioorganic & medicinal chemistry letters 2020 Sep 01

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Targeting the SMAD3 protein is an attractive therapeutic strategy for treating cancer, as it avoids the potential toxicities due to targeting the TGF-β signaling pathway upstream. Compound SIS3 was the first selective SMAD3 inhibitor developed that had acceptable activity, but its poor water solubility limited its development. Here, a series of SIS3 analogs was created to investigate the structure-activity relationship for inhibiting the activation of SMAD3. On the basis of this SAR, further optimization generated a water-soluble compound, 16d, which was capable of effectively blocking SMAD3 activation in vitro and had similar NK cell-mediated anticancer effects in vivo to its parent SIS3. This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Nannan Wu, Guangyu Lian, Jingyi Sheng, Dan Wu, Xiyong Yu, Huiyao Lan, Wenhui Hu, Zhongjin Yang. Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent. Bioorganic & medicinal chemistry letters. 2020 Sep 01;30(17):127396