Center Directors
Alanna Schepartz, Ph.D.
William Jorgensen, Ph.D.

The Problem

There are at least 100,000 different proteins existing in human cells, and a significant portion of them participate in complex protein signaling networks. Protein-protein interactions (PPI) are critical in transmitting signals that direct cells to carry out important biological functions. When these proteins behave abnormally, they can send out wrong signals that may result in uncontrolled cell growth and division, or cancer. An effective approach to fight cancer is to design new drugs that prevent abnormal PPI. If scientists can block the passage of wrong signals within the cell, they will be able to induce cancer cell death or stop cancer growth.

Still, developing small molecule PPI inhibitors remains one of the biggest challenges in drug discovery. Currently, the best available PPI inhibitors are α-peptides, which are small natural building blocks of human proteins. Designed α-peptide inhibitors interact with their targeted proteins and effectively block specific PPI, preventing the transmission of abnormal cancer-related signals. Unfortunately, α-peptides have limited clinical utility. One of the main reasons is that they can be easily digested by cellular enzymes, making them very unstable inside the cells. This poses an urgent need for the development of new and clinically applicable PPI inhibitors.

The Solution:

Drs. Alanna Schepartz and William Jorgensen, Director and Co-Director of the NFCR Center for Anti-Cancer Drug Design and Discovery at Yale University, are the leading scientists in designing new PPI inhibitors for the treatment of cancer and other diseases. Dr. Jorgensen is an expert in computational drug analysis, and Dr. Schepartz is a frontrunner in experimental drug design and discovery. The powerful collaborations of their research teams in the Center have led to the discovery of a new class of PPI inhibitors, the β-peptide.

Like α-peptides, β-peptides are small molecules which can bind to their target proteins specifically and effectively. Unlike α-peptides, however, β-peptides are not naturally existing molecules, therefore are not easily digested by cellular enzymes. This property confers β-peptides an incomparable advantage - it makes them stable inside the human body, resulting in long-lasting therapeutic effectiveness. In addition, it is possible to design and synthesize β-peptides to block almost any protein-protein interactions.

The Research:

Currently, Dr. Schepartz and Dr. Jorgensen’s research teams are focusing on designing and discovering β-peptide inhibitors of several cancer-related proteins, including c-Myc, hDM2 and Bcl-2. These proteins have been shown to play critical roles in the development of breast, prostate, digestive tract cancers, leukemia, and many other types of cancer. In addition, researchers in the Center are optimizing the size and structure of β-peptides to improve their bioavailability and other pharmacological properties. Successful designing and synthesis of β-peptide inhibitors of cancer-related proteins may lead to new anti-cancer drugs, bringing significant improvement in cancer treatment.