Drugging Cancer’s Big Four

Darryl McConnell Ph.D.
Research Site Head, Vienna, Austria

In the early 1980s, when I just started taking my first chemistry classes in high school, we knew what the four biggest causes of cancer were – RAS, P53, MYC and beta-Catenin. These proteins are found in the human body, and when mutated, cause more than half of all cancers. Medicines that target these four proteins have the potential to transform life expectancy for most patients with cancer. These proteins play such critical roles in the life of the cancer cell and have proven so elusive in drug discovery that scientists have given them descriptive names such as, the “beating heart of cancer” (RAS), the “guardian of the genome” (P53) and the “master regulator” (MYC). Beta-Catenin is of such central biological importance that it even has its own “destruction complex” to ensure that it stays under control. Sadly, after more than 30 years of research, there are no drugs approved today against any of the “big four”. Drugging the “big four” is such a challenging and compelling aspiration that no chemist wanting to bring more innovation to chemistry should shy away from.

Cancer is a disease of our genes with more than 100 different types of known cancers. In most cases, mutations in our genes accumulate over a period of 30 years and allow cancer cells to divide faster, become immortal and evade our immune system. The genome of cancer cells, unlike healthy cells, is inherently unstable. It contains up to a mind-boggling one trillion mutations, but only a few of these mutations actually drive the cancer. The remaining mutations are merely passengers. Mutations in RAS, P53, MYC and beta-Catenin are known to be the main drivers of cancer. RAS- driven cancers, for example, make up around 20% of all cancers, including almost all pancreatic cancers as well as more than 30% of lung cancers and almost half of all colon cancers.

Classical drugs work like “keys” that fit into “locks” on the surface of disease-causing proteins and turn them off. No classical drugs have been found for the “big four” because they do not have “locks” on their surfaces. RAS, P53, MYC and beta-Catenin function through interacting with other proteins via large, flat, complementary surfaces and thus require a new class of drugs that scientists are calling Protein-Protein Interaction Inhibitors. The conundrum of how to make a “key” when there is no “lock” has led to the belief that RAS, P53, MYC and beta-Catenin are “undruggable”. However, modern chemical approaches are challenging this dogma. After much insight and determination, these high hanging fruits of cancer research are now within reach.

At Boehringer Ingelheim, we have been able to discover “locks” on all the proteins we have explored so far using small pieces of drug molecules called “fragments”. Fragments provide a foothold for discovering drugs against proteins like the “big four,” but are just the very beginning in the drug discovery process. Developing these fragments into drugs has been made possible through developments at the juncture of biology, chemistry and physics. Using highly sensitive biophysical measurements, we are now able to detect almost any molecule that comes into contact with the surface of a protein. In addition, chemists are now able to generate three-dimensional photographs of protein-drug complexes (“lock and key”), where each individual atom is clearly visible. These photographs, called X-ray crystal structures, transform our chemists into atomic locksmiths able to precisely design the drug molecules of the future. I’m often asked, “What do we do if we fail to obtain X-ray crystal structures”? My answer is always, “We keep trying”. So far, we have always found a way. In fact, we have over 400 such photographs of KRAS itself –– a KRAS movie if you will. This truly transforms our ability to design drugs.

Modern drug discovery is not performed behind the closed doors of a pharmaceutical company, but in collaboration with the world’s academic leaders in the field. We are proud to have a growing network of collaborators who are also dedicated to making a big difference in the lives of patients, and who share our passion to drug the (so-called) undruggable. Our scientific interests and philosophies overlap so much with Professor Stephen Fesik and his team at Vanderbilt University, that we now have three key drivers of cancer on our list to develop drugs for – RAS, SOS and MCL1.  Together, with Alessio Cuilli and his team at the University of Dundee, we are investigating a completely new class of drugs called Proteolysis Targeting Chimeras (PROTACs), which represent one of the biggest innovations in chemistry in recent years.  Just a few kilometers from our research site, we are collaborating with Professor Robert Konrat and his group at the Max-Perutz Laboratories at the University of Vienna on arguably the most difficult class of proteins to drug –– the so-called intrinsically disordered proteins such as MYC. 

This is the first of a series of articles that will take a closer look at each of the “big four,” highlighting scientific breakthroughs and describing how Boehringer Ingelheim is drugging cancer’s big four in our pursuit of making cancers a chronic disease or dare it be said…curing cancers.