6 minute read
May 18, 2023

A Cross-Functional Mindset in DMPK

Drug Hunter Team

Dian Su’s journey from chemistry and proteomics to the DMPK of drug conjugates

Following a different path comes naturally to Dian Su, Senior Director of DMPK at Bicycle Therapeutics. From a childhood in a small village in China’s northeast Shandong province to her work examining the drug metabolism and pharmacokinetics (DMPK) of antibody-drug conjugates (ADCs) and Bicycle toxin conjugates® (BTCs), Dian has always looked to forge something new. Drug Hunter recently caught up with her as she discussed the path that led her away from rural life in a remote village, the background in chemistry that gave her a leg up, and how she leverages diversified training in establishing DMPK strategies.

About Dian

“I grew up in a village famous for its Fuji apples. Both my parents were farmers. Going to college was a luxury for someone in the area, not to mention girls.” Dian recalls. “But I didn’t want to take that as my fate.”

Dian eventually made her way to Shanghai, where she encountered a much bigger world while earning degrees in pharmaceutical engineering and medicinal chemistry. She seized the opportunity to pursue a higher degree in the U.S., researching DNA photoproducts related to skin cancer. PhD in hand, she then expanded her skill set to include proteomics. Her interest in research landed her a job at Genentech, where she focused on ADCs—and learned other skills critical to her career. It was the chance to “build something new” that led Dian to Mersana Therapeutics and now Bicycle Therapeutics to leverage her experience and build out the DMPK group.

“ADCs were the hottest area when I started working at Genentech, and I worked with a really comprehensive, high-performing team,” Dian explains. “We always say it takes a village, and that’s what happened. I not only learned the ADC area, but I learned so much from colleagues beyond my function. To collaborate with people from other functions, e.g., chemistry, biology, pharmacology and toxicology, to learn to speak the same ‘language’—this kind of cross-functional training is really important.”

As the ADC team moved toward a greater emphasis on development, Dian felt the pull to return to her “research mindset” and switched paths again, this time delving into DMPK, particularly small molecules and peptides. “I accessed this opportunity to contribute to new modalities, like macrocyclic peptides,” says Dian. “It built my confidence to build something from scratch.”

A chemistry background is an advantage in DMPK …

Dian thinks that her chemistry background is a boon. “Chemistry has allowed me to understand DMPK concepts faster and maybe at a deeper level because, in the end, it’s all about the transformation of chemical structures,” Dian notes. Including structures and highlighting biotransformations, for example, helped colleagues understand a given platform as new payloads were incorporated, especially the ability to illustrate how a chemical structure changed with the introduction of a new linker payload.

“A picture is worth a thousand words,” she says, adding that it became easier to identify the critical path in the biotransformation. “Without understanding the structure, every mass may look the same and play the same importance; once you have the metabolites’ structures you know which biotransformation is more critical to PK, efficacy, and/or toxicity behaviors.”

...and a proteomics background is a plus:

Proteomics is a special gift to Dian, particularly after it helped her identify one of the most surprising biotransformations she’s seen, one that involved a protein adduct following hydrolysis. 

In the beginning of the project, Dian’s team witnessed something “very unusual” in the ADC biotransformation assay, which they “had no clue what it could be.” It could have been some residual DNA, or maybe a protein, but they knew it was something big due to the 24 kDa change in mass of the ADC. Dian decided to take a “bold and lucky guess” and try using proteomics to see if she could confirm her suspicion of some kind of protein adduct. “Everything happens for a reason,” Dian says. “Remember my post-doc research? Proteomics! Just because of that experience, I had expertise in proteomics and it was relatively easy to identify the unknown protein” which was creating the adduct.

In her small molecule DMPK research, proteomics also served to identify reactive metabolites (e.g., formation of GSH adducts) in MetID (metabolite identification) profiling. Perhaps most important, Dian says it was proteomics that set the stage for her participation in building macrocyclic  peptide platforms at Genentech which she calls “a new era in DMPK.”

Fascinated by the world of reactive metabolites:

Dian finds reactive metabolites particularly intriguing: “It’s interesting how reactive metabolites can contribute to toxicity and sometimes have no, or minimal, impact. At a general level, a reactive metabolite is something that people easily blame when they see toxicity. But when you dive in to see the mechanism, you can examine the chemical structure of that specific reactive metabolite to see whether it translates into a toxic metabolite. If you see a reactive metabolite, how do you judge it? Does it raise a bigger risk, or is it okay to keep going ?—I think that is a most interesting and challenging area.”

vcMMAE: the magic molecule

“My favorite molecule would have to be vcMMAE because it’s a pioneer linker payload for the drug conjugate world. They are very promising therapeutics, and vcMMAE opened up an avenue for the field. It’s such an effective tubulin binder; that’s the MOA of the molecule—you link it to the antibody and that’s the antibody-drug conjugate. The beauty of vcMMAE is that it can serve as a platform molecule, meaning you can use the same linker drug to target different diseases.

A mentor who inspired her:  

Dian was inspired most by a mentor who built a high-performing team, and his gift was to treat everyone equally. He created a space where everyone’s input was valued: no matter what level you were at, you felt safe to ask questions and to answer other people’s questions. He emphasized mechanistic understanding, which helped us more thoroughly understand the PK/PD behaviors.”

Thank you, Dian for sharing your story and adventures in drug conjugates with us!

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