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Chemical Biologists Create Small Molecules to Boost Discoveries or Prototype Novel Therapies

From Paths of Progress 2019

By Eric Bender

Tiny stapled peptides (in yellow) bind to alpha-helical peptides (red) to help them maintain their helical structure, bind tightly to their targets, and resist degradation in the body. This process may help doctors more effectively deliver drugs where needed.

Biomedicine always comes down to biochemistry – the exact chemical interplay between the dizzying number of molecules that drive health or disease. In every cancer research center, biochemists study these interactions, develop chemical tools, and collaborate with molecular biologists, genomicists, and other experts in biomedical science.

Within this vast field, chemical biologists focus primarily on designing and synthesizing small molecules for research and treatment. Back in 2006, Dana-Farber launched a bold experiment to accelerate this work: It hired three chemists with ambitious goals and gave them access to resources not usually found in academia.

One hope for the budding Chemical Biology program was that the chemists, in partnership with Dana- Farber physician-scientists, would be able to unlock some of the mysteries that drive cancer.

"A good chemical probe can do a lot for the basic biological understanding of a process, and it's often very complementary to genetic tools," explains Program Director Milka Kostic, PhD. "In genetic research, you usually remove the entire gene. With a chemical compound, you inhibit the activity of the protein, or remove the protein rather than the gene. So that offers you very complementary ways of asking about the function of a protein."

The experiment proved a wild success. By 2015, the first three investigators had published more than 300 papers, filed more than 250 patents, formed eight startup firms, and, most importantly, made major contributions to the creation of six drugs in clinical trials. Two of the drugs, ceritinib and osimertinib, were approved by the Food and Drug Administration (FDA) in 2014 and 2015 for treating non-small cell lung cancer.

Today, the Institute's Chemical Biology program hosts nine principal investigators and more than 100 researchers. Its headquarters, in state-of-the-art facilities at Dana-Farber's Longwood campus, brings together Institute chemists, structural biologists, translational research experts, and other experts under one roof.

Investigators often take on challenges that most academic chemists might not. "We're much more engineering-focused, working on the problems that are in front of us versus trying something new and then hoping that somebody cares about what we did," says Nathanael Gray, PhD, one of the program's first three members.

Another goal for the burgeoning Chemical Biology program was for investigators to connect the dots between basic academic research and drug development – since many promising findings in academic chemistry labs are reported in the literature without ever receiving serious attention from drug companies.

"Our unique ecosystem here lets us work on problems that are more difficult or are at an earlier stage of development," Gray says. "We also work on rare cancers where the commercial case for development can't be made at this point but the biological rationale for research is strong."

Nathanael Gray, PhD, was one of the first members of Dana-Farber’s Chemical Biology program, which now hosts nine principal investigators and more than 100 researchers.

Pursuing Peptides

One promising example of applying innovative chemistry to decipher cancer mechanisms and develop a new class of therapies is the "stapled peptide" technology. The potential utility of this approach in cancer research and drug development emerged from a collaboration between Gregory Verdine, PhD, of Harvard University, the late Stanley Korsmeyer, MD, of Dana-Farber, and then-postdoctoral fellow in Pediatric Hematology/Oncology, Loren Walensky, MD, PhD.

As small subcomponents of proteins, peptides can often recapitulate key biological features of the original protein. The design of stapled peptides begins with natural peptides that have the shape of an "alpha-helix."

Alpha-helical peptides have a distinctive structure that has evolved to bind tightly to specific protein targets. Peptide drugs shaped as alpha-helices, in theory, might target and disrupt protein interactions that drive cancer far more selectively and effectively than small-molecule compounds because the peptides are already evolutionarily honed to be a perfect match to the protein target, similar to a key fitting into a lock.

However, alpha-helical peptides removed from the context of the natural protein can lose their shape and biological function, and they can also get rapidly chewed up in the blood before reaching their intended targets.

Stapled peptides aim to solve these problems by chemically inserting struts into alpha-helical peptides, enabling them to maintain their helical structure, bind to their targets even more tightly, resist degradation in the body, and effectively enter cells and operate like a drug, says Walensky.

Walensky began working on the technology in the Korsmeyer lab in 2000. He opened his own lab in 2006 as one of the Chemical Biology program's first members, and has steadfastly and meticulously advanced this research ever since.

Sara Buhrlage, PhD, of the Chemical Biology program, leads a laboratory working to develop first-in-class drugs and bring them to use in patients.

Following up on discoveries from his lab and others, the startup biotechnology company Aileron Therapeutics has brought the first stapled-peptide drug into clinical trials for cancer. Aileron's ALRN-6924 drug candidate is designed to unleash the p53 protein, one of the most prominent natural tumor suppressors, in cancers where the protein is intact but otherwise blocked from exerting its anti-tumor role. The drug is under study for treating a series of adult and pediatric cancers. In fact, ALRN-6924 is being tested in the very first clinical trial of its kind in children, with the goal of reactivating the p53 tumor suppressor pathway in a host of childhood leukemias and solid tumors.

This pediatric trial was kicked off by a research partnership between Walensky and his Dana-Farber colleague Kimberly Stegmaier, MD. Genomic screening and therapeutic testing by the Stegmaier and Walensky labs indicated that many pediatric cancers with normal p53 protein might be vulnerable to the stapled-peptide strategy advanced by Walensky and Aileron. Follow-up tests in cells and mice confirmed the therapeutic potential of their findings. Attending one of Stegmaier's lab meetings, clinical researcher Steven DuBois, MD, MS, heard about the results and immediately envisioned a clinical study, which opened in November 2018.

"This research exemplifies our mission to traverse the complete arc from chemical biology discovery to clinical translation," says Walensky. "It is a long and challenging path that requires laser focus and persistence, but if we can bring new drugs to patients as a result, then it is worth every minute.

"Although ALRN-6924 is currently at the earliest stage of testing in the clinic, we are hopeful that stapled peptides could represent an entirely new treatment modality for relapsed pediatric cancers."

Taking Compounds to the Clinic

Researchers in Dana-Farber's Chemical Biology program made major contributions to the development of ceritinib and osimertinib, targeted therapies approved by the Food and Drug Administration for non-small-cell lung cancer. Here are some other drug candidates, also pioneered at least in part by program investigators, now in clinical trials.

  • Aileron Therapeutics ALRN-6924, a stapled-peptide drug. In trials for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), peripheral T-cell lymphoma, Ewing sarcoma, and other adult and pediatric cancers.
  • Medivir remetinostat, which inhibits enzymes that wrap up DNA tightly in chromosomes. In trials for cutaneous T-cell lymphoma and basal cell carcinoma.
  • Novartis ABL 001, which targets a different region of the BCR-ABL protein (which is mutated in chronic myelogenous leukemia, CML) than previous drugs. In a trial for CML.
  • Roche RO6870810, which inhibits members of a family of proteins known as BET that are key players in cancer biology. In trials for AML, diffuse large B-cell lymphoma, multiple myeloma, MDS, ovarian cancer, triple-negative breast cancer, and various advanced solid tumors.
  • Syros Pharmaceuticals SY-1425, designed to inhibit "super-enhancer" genes that can drive cancer cell growth. In a trial for AML and MDS.
  • Syros Pharmaceuticals SY-1365, a first-in-class selective inhibitor of a protein known as CDK7 involved in two processes that drive cancer. In a trial for ovarian and breast cancers.

Other startup companies that exploit findings from the program are working on drugs that have yet to enter clinical trials. One firm is C4 Therapeutics, which is creating drug candidates that employ targeted protein degradation. Another is WntRx Pharmaceuticals, which generates stapled-peptide inhibitors of a protein thought to be implicated in brain, breast, colorectal, liver, lung, and ovarian cancers.

Breaking Problematic Proteins

Another major effort is underway in "targeted protein degradation," in which compounds are designed to destroy rather than inhibit proteins that are key targets in disease.

There is a curious history for this therapeutic approach. It begins in part with thalidomide, an oral drug first and forever notorious for causing tragic birth defects in thousands of babies. Years later, thalidomide and similar compounds quietly became mainstays for treating multiple myeloma, although it wasn't well understood how these drugs work.

Eric Fischer, PhD, helped to solve this puzzle by establishing the crystal structure of thalidomide and how it binds to its molecular target. Related work in labs around the world eventually showed that thalidomide acts by degrading proteins that go wrong in multiple myeloma.

A stapled peptide drug based on research by Loren Walensky, MD, PhD, is currently undergoing clinical testing to treat a wide range of cancers.

Protein degradation is a normal part of cell life; a small protein called ubiquitin acts as a tag that marks proteins for routine disposal. But in cancer cells, this routine disposal often fails. Better understanding of this process offers striking new possibilities for targeted therapies.

"It's a conceptual change, a new treatment modality," says Fischer, who joined Dana-Farber in 2015. "We can think more creatively about therapeutics and go after targets within the cell that have been previously considered undruggable."

"Essentially, you're tricking the cell into thinking specific proteins should be degraded when naturally they wouldn't be degraded," Gray explains. By doing that, the theory goes, you can effectively turn on the routine disposal process, allowing cancer cells to die.

"This is opening up a huge new realm of potential molecular targets that we couldn't touch before, either because we didn't know what their function was or because they didn't have a nook and cranny where a small molecule could bind," he says.

In November 2018, Dana-Farber announced that Gray and Fischer will lead the new Center for Protein Degradation, a partnership with healthcare investment firm Deerfield Management. "Many labs at Dana-Farber and in the larger Longwood Medical Area want to collaborate with us to translate their findings into potential therapeutics," Fischer says. "The Center for Protein Degradation will give us the resources to do this properly."

"The primary purpose of the center is to invent the protein degrader technology of tomorrow, and then to deploy it," Gray says. "We don't actually know the best approaches for finding these molecules, because they defy a lot of the logic around conventional small molecule inhibitors, and so that makes discovering them and optimizing them quite different. We're at the tip of the iceberg with this technology."

Kimberly Stegmaier, MD (left), and Eric Fischer, PhD (right), lead research looking into new ways that cancers might be vulnerable to stapled-peptide strategies and other targeted therapies.

Collaboration in Translation

Chemical biologists have established a dense web of research collaborations with other scientists at Dana-Farber and the greater biomedical research world, helping to push therapies toward the clinic.

Sara Buhrlage, PhD, for example, is researching "deubiquitylating enzymes" (DUBs), proteins that can remove the ubiquitin tags that mark a protein for degradation. By targeting these enzymes, one could in theory prevent the removal of the ubiquitin tags, thus allowing for normal protein degradation and cell death.

She gives one example of joint work that was, in fact, kicked off by the same genomic research from Kimberly Stegmaier's lab that contributed to the clinical trial of the Aileron stapled-peptide drug for pediatric patients.

The genomic screening identified one DUB as a promising target for Ewing sarcoma, a pediatric solid tumor. However, scientists in the Stegmaier lab couldn't confirm the result in cells with existing chemical probes.

But a compound from the Buhrlage lab that performed more cleanly clearly confirmed the genomic results. "That finding was added to Kim Stegmaier's paper, and we've gone on to develop even better compounds for treating Ewing sarcoma with her," Burhlage says.

"Dana-Farber is a wonderful place to work as a chemist and be able to do this translational research side-by-side with the world's expert in whatever cancer you want to work on," she adds. "We routinely talk to clinicians who just did their rounds, and we see patients when we go to the cafeteria. Even those of us who are working in early research stay focused on better treatment options for patients. It's all about getting to an answer."

Other Feature Stories from Paths of Progress 2019

  • Wrench in the Works

    Stopping cancer's mechanism of cell division with new drugs known as CDK4/6 inhibitors.

  • Natural Killer Cells

    Natural killer cells are the first wave of defenders against infection, and they may have a new role in treating cancer.

  • Cancer, Interrupted

    Uncovering new strategies for identifying signs of pre-cancer – and stopping it before it starts.

To see the entire publication, please download the PDF version

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Disclosure of Advisory Roles and Certain Industry Support

See an overview of relevant board memberships, outside support, and significant advisory roles as reported by several physicians and researchers featured in the 2019 issue of Dana-Farber's Paths of Progress magazine.