Oncotarget

Research Papers:

Disruption of Myc-Max Heterodimerization with Improved Cell-Penetrating Analogs of the Small Molecule 10074-G5

Huabo Wang, Jay Chauhan, Angela Hu, Kelsey Pendleton, Jeremy L. Yap, Philip E. Sabato, Jace W. Jones, Mariarita Perri, Jianshi Yu, Erika Cione, Maureen A. Kane, Steven Fletcher, Edward V. Prochownik _

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint  |  This article has been corrected. Oncotarget. 2018; 9:35196.

Oncotarget. 2013; 4:936-949. https://doi.org/10.18632/oncotarget.1108

Metrics: PDF 1173 views  |   HTML 1122 views  |   ?  


Abstract

Huabo Wang1, Jay Chauhan2, Angela Hu1, Kelsey Pendleton1, Jeremy L. Yap2, Philip E. Sabato3, Jace W. Jones2, Mariarita Perri4, Jianshi Yu2, Erika Cione4, Maureen A. Kane2,5, Steven Fletcher2,5 and Edward V. Prochownik1,6,7

1 Section of Hematology/Oncology, Children’s Hospital of Pittsburgh of UPMC

2 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

3 PharmD Program, University of Maryland School of Pharmacy, Baltimore, MD, USA

4 Department of Pharmaco-Biology, University of Calabria, Rende (CS), Italy

5 University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA

6 Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine

7 The University of Pittsburgh Cancer Institute, Pittsburgh, PA

Correspondence:

Edward V. Prochownik, email:

Steven Fletcher, email:

Keywords: 10058-F4, 10074-G5, intrinsically disordered proteins, JQ-1, BRD4

Received: May 31, 2013 Accepted: June 21, 2013 Published: June 22, 2013

Abstract

The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 1108