1. Academic Validation
  2. Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors

Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors

  • Bioorg Med Chem. 2021 May 15;38:116114. doi: 10.1016/j.bmc.2021.116114.
Yonglei Zhang 1 Xiaomin Xie 1 Xueyuan Wang 2 Tiantian Wen 2 Chi Zhao 2 Hailong Liu 2 Bo Zhao 3 Yongqiang Zhu 4
Affiliations

Affiliations

  • 1 National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210023, PR China.
  • 2 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China.
  • 3 National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210023, PR China. Electronic address: zhaobo@njnu.edu.cn.
  • 4 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China. Electronic address: zhyqscu@hotmail.com.
Abstract

Valine-containing protein (VCP) is a member of the adenosine triphosphate family involved in a variety of cellular activities. VCP/p97 is capable of maintaining protein homeostasis and mediating the degradation of misfolded polypeptides by the ubiquitin-proteasome system (UPS). In this manuscript, a series of novel p97 inhibitors with pyrimidine as core structure were designed, synthesized and biologically evaluated. Based on the enzymatic results, a detailed structure-activity relationship discussion of the synthesized compounds was carried out. Furthermore, cellular activities of the compounds with enzymatic potency of less than 200 nM were investigated by using A549 and RPMI8226 cell lines. Among the screened inhibitors, compound 17 (IC50, 54.7 nM) showed good enzymatic activity. Investigation of cellular activities with non-small cell lung Cancer A549 and multiple myeloma (MM) RPMI8226 further confirmed the potency of 17 with the IC50 values of 2.80 μM and 0.86 μM, respectively. Compound 17 is now being developed as a candidate. Finally, docking studies were carried out to explore the possible binding mode between the active inhibitor 17 and p97.

Keywords

Biological activity; Boric acid; Molecular docking; Ubiquitin–proteasome system; Valine-containing protein.

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