Novel Small Molecule p53/mdm2 and p53/mdm4 Antagonists

The tumor suppressor protein p53 has vast control over cancer-related processes, and negative regulation of p53 can drive the onset of carcinogenesis. Two regulatory proteins, Mdm2 and Mdm4, attach directly to p53 and interfere with p53’s tumor suppressor activity. Development of strategies to pharmacologically target Mdm2 and Mdm4 could relieve suppression of p53, and allow for rescue of p53’s potent tumor suppressant activity in patients.Mdm2/4 inhibitors have been closely pursued by the pharmaceutical industry, and several candidate compounds are currently being evaluated in phase 1 clinical trials. But, there is still a major need for drug discovery in this area due to the poor pharmacologic properties of some of these candidate compounds. Furthermore, even if current therapeutics proceed towards the clinic, development of new and diverse forms of Mdm2/4 antagonists will be required to combat drug resistance. To address this need, researchers at the University of Pittsburgh have created and validated novel antagonists of Mdm2/4.

Description

This technology includes several classes of antagonists that disrupt interaction between p53 and Mdm2 or Mdm4, potentially rescuing p53 tumor-suppressive activity. These compounds were identified through a large digital screening assay, and are predicted to bind directly to the p53 binding site within Mdm2 or Mdm4. Following synthesis, attachment of these compounds to this predicted binding site was confirmed experimentally, and the tested antagonists showed strong binding to Mdm2 or Mdm4. In one case, a tested compound displayed higher binding efficiency than Nutlin-3a, which is a known Mdm2 antagonist currently being evaluated in clinical trials. Compared to other current Mdm2/4 antagonists, these novel compounds also exhibit improved pharmacologic properties, including improved metabolic stability, water solubility, and cell permeation. Finally, in vitro testing of proposed Mdm2 and Mdm4 antagonists showed the induction of cell death in cancer cells, suggesting therapeutic potential.

Applications

· In treatment of cancer

Advantages

· Compounds are easily synthesizable, supporting rapid and inexpensive production
· Exhibit improved pharmacology and cellular activity compared to several current antagonist in development
· Antagonists bind strongly and specifically to Mdm2 or Mdm4
· Compounds block recruitment of p53 to Mdm2 or Mdm4, rescuing p53 tumor suppressive activity

Invention Readiness

In vitro data

IP Status

https://patents.google.com/patent/US8163789B2; https://patents.google.com/patent/US9187441B2

Related Publication(s)

Koes, D., Khoury, K., Huang, Y., Wang, W., Bista, M., Popowicz, G. M., Wolf, S., Holak, T. A., Dömling, A., & Camacho, C. J. (2012). Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists. PLoS ONE, 7(3), e32839. https://doi.org/10.1371/journal.pone.0032839

Surmiak, E., Neochoritis, C. G., Musielak, B., Twarda-Clapa, A., Kurpiewska, K., Dubin, G., Camacho, C., Holak, T. A., & Dömling, A. (2017). Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction. European Journal of Medicinal Chemistry, 126, 384–407. https://doi.org/10.1016/j.ejmech.2016.11.029

Estrada-Ortiz, N., Neochoritis, C. G., Twarda-Clapa, A., Musielak, B., Holak, T. A., & Dömling, A. (2017). Artificial Macrocycles as Potent p53–MDM2 Inhibitors. ACS Medicinal Chemistry Letters, 8(10), 1025–1030. https://doi.org/10.1021/acsmedchemlett.7b00219