By Patrice L. Jackson-Ayotunde and Steven Fletcher
Cancer is a complex disease that is initiated by gene-environment interactions and perpetuated by a complex network of signaling pathways within the cell. Accordingly, successfully tackling such a complicated disease state often demands the administration of a cocktail of chemotherapy drugs. Many chemotherapy regimens are associated with severe side effects due to a lack of target specificity and/or an inability to discriminate cancerous cells from healthy cells. A focused polypharmacology strategy in which a single drug is engineered to form a blockade at two or more different protein targets is a promising approach toward more effective and less toxic chemotherapy agents.
The Bcl-2 family of proteins regulates programmed cell death, or apoptosis. In a range of cancers, the anti-apoptotic Bcl-2 proteins, such as Bcl-xL and Mcl-1, become upregulated, granting the cell immortality through sequestration and neutralization of their pro-apoptotic counterparts, such as Bak and Bax. The p53 transcription factor also promotes apoptosis, in part through the transcription of pro-apoptotic Bcl-2 proteins. However, the activation of p53 is tightly controlled by the ubiquitin ligase MDM2, and in many cancers, elevated levels of MDM2 ensure p53 is deactivated and labeled for destruction. The disruption of these protein–protein interactions (PPIs) with selective small-molecule inhibitors has been demonstrated, although compensatory upregulations of sister proteins and of other pathways are evasive manifestations that continue to plague drug efficacy. Interestingly, the PPIs between pro- and anti-apoptotic Bcl-2 proteins and p53/MDM2 are governed by similarly-functionalized alpha-helical domains of the pro-death partners.
Therefore, towards next-generation and potent chemotherapeutics, the development of small-molecule alpha-helix mimetics that simultaneously mimic key residues of both the BH3 alpha-helix of pro-apoptotic Bcl-2 proteins and the helical transactivation domain of p53 can potentially relinquish both families of cell-killing proteins from their captors. In this way, multiple pro-survival proteins will be inhibited with a single molecule, an especially lethal antineoplastic agent.
This is just one of the topics that will be discussed at the AAPS DDDI section 2nd regional meeting this year at the University of Maryland School of Pharmacy in Baltimore, on Friday, August 4, 2017. The meeting, entitled Evolving Strategies for Drug Candidates Optimization in a Changing Pharmaceutical Landscape, is a focused forum for drug discovery and preclinical scientists in the pharmaceutical field to discuss the most relevant topics in drug design and discovery and an excellent networking opportunity for attendees. The meeting agenda has been strategically assembled to address current, novel, and future strategies for drug candidate selection, and speakers have been selected to cover all discovery and preclinical (chemistry, pharmacology, ADME, pharmaceutical sciences, analytical chemistry, and toxicology) disciplines, and multiple sectors (industry, academia, and regulatory agencies). This diverse strategy—the organizers hope—will allow for sharing of best practices and approaches across organizational borders and hence contribute positively to the scientific field of drug candidate selection. This will also be a great opportunity for student attendees who are interested in careers in the biopharmaceutical arena to learn about the advancements and challenges in drug discovery and to interact with the guest speakers and other pharmaceutical scientists.
Learn more about the event, the speakers, the organizing team, and online registration on the AAPS DDDI Regional Meeting 2017 webpage.