Protein Homeostasis and MLN4924: another proof point of Millennium leadership in UPS
Millennium is recognized as the scientific leader in protein homeostasis, a research area that has its roots in Nobel-Prize winning science. There are a variety of disease states, notably cancer, in which the homeostatic balance of cellular proteins can be altered permanently, threatening survival of the host.
Protein homeostasis is today what kinases were to the science of drug development in the mid-eighties. It opens a similarly vast frontier for drug development for many disease states with special emphasis in anti-cancer therapeutics. The success of VELCADE has validated this area of exploration. The success of pre-clinical work reported in Nature for MLN4924 is another proof point of Millennium's commitment to fully exploring this area of discovery, and the now ongoing Phase I clinical study of MLN4924 in patients with cancer to investigate the safety of this investigational drug.
Our ongoing collaboration with Harvard Medical School to conduct joint research in protein homeostasis will build on the already significant expertise of both institutions, accelerating our R&D in this important area of cancer biology.
Video Transcript
Millennium Publishes Preclinical Data in Nature
The NEDD8-Activating Enzyme
In most human cells, proteins are constantly being created and destroyed, and this occurs in a very highly controlled way. And as leaders in protein homeostasis, we've had a longstanding interest in the enzymes that regulate protein homeostasis. That is the enzymes that make up the Ubiquitin Proteasome System.
Now we know that if we inhibit the proteasome, which is the last step in the UPS, that we block the turnover of a significant portion of proteins in the cell and that this leads to cancer cell death. But we also know that there are enzymes upstream of the proteasome that more selectively regulate protein turnover, and Millennium is keenly interested in many of these enzymes as potential drug targets. And one of these enzymes is NEDD8-Activating Enzyme, or NAE.
Discovery of MLN4924
So several years ago, we discovered that NAE regulates the turnover of an important subset of the proteins that are degraded by proteasomes and that many of these proteins have important roles in cancer cell growth.
An internal program was set up to identify small molecule inhibitors of NAE and to understand the biological consequences of shutting down NAE in cultured cells and then in laboratory animals.
Ten years of work by Millennium scientists has come to fruition with the identification of MLN4924. It's a first-in-class NAE inhibitor, which is an investigational drug currently in Phase I clinical trials for the treatment of patients with cancer.
Findings Discussed in the Nature Paper
So the Nature article reports on the research that provided the preclinical rationale for the advancement of this molecule into human trials. Our initial studies evaluating the mechanism by which MLN4924 acts in cells, we show that MLN4924 only inhibits NAE-mediated proteolysis, which differentiates it significantly from proteasome inhibition and thus suggests that it is more selective.
Additionally, we made the unexpected discovery that NAE inhibition induces death in many different types of cancer cells by blocking the turnover of certain modulators of DNA synthesis. This leads to uncontrolled DNA synthesis in the cancer cells, which leads to significant DNA damage and cancer cell death.
Importantly, we show that in animal models of human cancer that MLN4924 stops tumor growth and that this is due to NAE inhibition. Our understanding of the mechanism of this molecule in vitro, in cultured cells, and in animal models has been translated into biological assays that are being used to drive the clinical development of MLN4924.
The Clinical Development Process for MLN4924
Over the past year and a half, Millennium's Preclinical and Clinical organizations have worked very closely together to study MLN4924 in Phase I clinical trials of patients with cancer. Our first step in the clinic is to understand how to administer this investigational drug safely to patients.
At the same time we apply our broad understanding of how this molecule works in animal models to understanding how it might work in patients.
We have a panel of assays, some of which are described in the paper, which allows us to determine how it will affect various tissues in the bodyÑincluding the blood, the skin and even the tumor.
Additionally, as we look to identify the optimal dose and schedule for MLN4924 we are guided by the preclinical data, which shows how various dosing schedules affect tumor growth in animals.
This information is key in understanding how to deliver it to patients and it's guiding our early clinical development in a range of cancers.
The continual discussions between Millennium's Preclinical and Clinical organizations is crucial in developing innovative new molecules. And we use the science from the lab and data from the clinic in concert in order to bring forward new medicines through clinical development.
