As a medicinal chemist, I hunt for compounds that show promise as potential drugs. I moved my research program to SRI International last year from a pediatric research hospital where I had the unusual experience for a medicinal chemist of working alongside clinicians on the front line of the cancer fight. I witnessed their frustration with currently available cancer treatments. For example, many recently developed anticancer drugs are therapeutic agents that only delay the progression of disease and require lifelong, expensive treatment regimens.
Molecular and genetic studies of cancer have clearly shown that cancers are actually a collection of many distinct diseases. To achieve durable curative chemotherapy with minimal side effects, we need drugs that treat the underlying causes of cancers. My goal is to discover molecules that will change the paradigm for cancer chemotherapy, for at least a significant subset of cancers. It will only be possible to treat all cancers by the discovery of many such drugs.
Toward this end, an intricate and poorly understood molecular machine that has played a role in my recent research career appears to have great promise as a new drug target class and is an Achilles’ heel for certain types of cancer. This molecular machine is called the spliceosome.
What is a Spliceosome?
that is read from a living organism’s DNA and then cuts and pastes—“splices”— it into various configurations while deleting unnecessary stretches.
In a nutshell, the spliceosome is a complex assembly of hundreds of proteins and RNA molecules. The spliceosome takes the RNA that is read from a living organism’s DNA and then cuts and pastes—“splices”—it into various configurations while deleting unnecessary stretches. This is one of the ways that organisms can create enormous variation in their proteins from the same information that is present in a single gene. (Discovering that eukaryotic genes are discontinuous, with stretches of coding DNA being interrupted by stretches of non-coding DNA, is one of the watershed moments in molecular biology.) The dysregulation of the splicing process can therefore play a critical role in certain human diseases.
In recent years, several bacterial metabolites have been identified that have antitumor activity linked to their interaction with the spliceosome in cancer cells. These compounds occur naturally, produced by bacteria that humans routinely encounter. Normal human cells may have evolved to have the ability to resist the effects of these natural products. Some tumor cells, however, appear to have let down their guard as they grow unchecked, like a parasite in a host. Like salamanders losing eyesight and going blind in a cave, it may be that some tumors lose such protective mechanisms because they are protected by our bodies’ immune systems. This vulnerability may be one reason that some tumors are susceptible to newly developed drugs that target the spliceosome. Whatever the cause of the observed vulnerability is, it represents an opportunity for medicinal chemists.
In my lab, we have created totally synthetic compounds, called sudemycins, which specifically kill some types of cancer cells at low doses of drug without harming normal cells. The most advanced prototype we have developed is called sudemycin D6, which targets the SF3B1 protein of the spliceosome.
One of the sea change moments in this area came with the publication of several independent reports on recurrent mutations of SF3B1 in patients suffering from the myelodyspastic syndromes, chronic lymphoblastic leukemia and a range of other cancers. This has led to significant interest in the application of sudemycin D6 in these cancers.
Triple-negative breast cancer is another application of sudemycin D6, and we are looking at many others, including whether it will work against lymphoma, melanoma and certain brain and colon cancers.
We still don’t understand the mechanism of tumor-selective toxicity, but that is an area of active collaborative research. For this reason we have been working to develop the right tools that allow us to understand how to design effective and safe dosing regimes, which will give clinicians the tools they need to advance this drug.
New Possibilities for Better Cures
There have been many advances in understanding the structure and mechanism of the spliceosome in recent years and the spliceosome has been big news in the scientific community. My interest in small molecules that act on the spliceosome has been validated. This area really excited me even when most others were not convinced, and it has now become clear as the spliceosome reveals its secrets that it offers many possibilities in the quest to develop better cancer therapies—that is, less expensive and more permanent. I think the spliceosome as a target opens one of the best new areas to come up with therapeutics that allow patients to enter a hospital with cancer and go home cured.
I am a co-author on a Nature paper that uncovers an important mechanism of selective action for compounds such as sudemycin D6 and shows its activity in cancer tumor models.
In September 2015, a report on a substantial part of the molecular architecture of the spliceosome was announced in the journal Science). An article in Chemical and Engineering News, for which I was interviewed, put the spliceosome on its cover.
Like many others, I have had my own personal exposure to cancer and its treatment, both as a cancer survivor and a caretaker for my wife, who survived triple-negative breast cancer. She was in a fortunate minority who showed a good response. However, during her therapy, we lost a good friend and colleague to the same disease. These experiences have fueled my passion to develop better, highly selective and potentially curative anti-tumor agents.
