Development of Orally Bioavailable Peptides Targeting Intra-cellular Potein: From a Hit to a Clinical KRAS Inhibitor
Ryuji Hayashi, PhD; Group Head, Discover Chemistry Department, Research Division, Chugai PHarmaceutical Co., Ltd.
Size matters in molecular medicine, according to Tokyo-based Chugai Pharmaceutical Co. Ltd., which says midsized cyclic peptides could hit the disease targets other drugs cannot reach.
Ryuji Hayashi, Ph.D., group head of discovery chemistry at Chugai, who spoke about the firm’s efforts at TIDES Asia in March told delegates the idea is to create peptide drugs than hit undruggable targets.
“Small molecules and antibodies have been the two giants in drug discovery in the last few decades, but there are some pros and cons,” Hayashi said.“Small molecules are great in terms of intracellular targeting, flexible administration route, but they are susceptible to target inhibition such as is caused by protein-protein interaction. On the other hand, antibodies are less challenged by target inhibition, but they are harder to administer. They also struggle to hit intracellular targets.”
These limitations mean drugs belonging to either of the two modalities can only hit about 40% of potential disease targets, according to Hayashi.
“So the question is, what about the rest? The 60% that’s left, and that’s where we are aiming for,” he said, adding that “midsized molecules can target GPCRs, iron channel signaling molecules, transcriptional factors, and so on.”
Cyclic Peptides
Chugai is focused on developing midsized cyclic peptides, which contain a circular sequence of bonds and form ring-like structures. These molecules offer major advantages for drug development Hayashi said, citing capacity for “induced fit” as an example.
“So the idea with induced fit is that targets without clear binding pockets can be targeted. If the midsized cyclic peptide has enough molecular weight, it can bind to [the] flat surface of the protein, generating the new pocket. And that’s attractive,” he said.
“Drug-like”
There are also potential advantages from a drug discovery viewpoint, according to Hayashi, particularly in terms of screening.
“Parallel synthesis is possible. If we establish good synthetic protocols, we can make tens of thousands of compounds rapidly. Then what we can do is identify the ‘drug-like’, midsize molecules.”
The use of drug-like criteria as a starting point is in marked contrast with traditional discovery practices, which focus on finding compounds that interact with a desired target — or “hits” — before assessing their physiochemical characteristics.
Hayashi said, “Often hits have good potency but poor drug-likeness. So we say ‘OK, we’ll improve the drug-likeness’ and start substituting amino acids. The problem is that while this causes drug-likeness to improve, it also causes significant structural changes — called scaffold hopping — that negatively impact activity.“This dilemma has been a headache for peptide drug discovery. So we thought, why don’t we start from drug-like hit to guide our midsize cyclic peptide drug discovery programs?”
To determine drug-like criteria, Hayashi’s team used the immunosuppressant cyclosporin A, a naturally occurring cyclic peptide, as a model.
Cyclosporin consists of 11 amino acids, seven of which are alkylated. The C log P is very high at 14.4, and it has molecular weight — all of which are desirable in a drug product, Hayashi said.“So using parallel synthesis, we made roughly 1,000 compounds randomly around cyclosporine and then assessed their permeability and metabolic stability using various assays. The result provided the team a threshold for drug-likeness for each characteristic.”
Chugai used these criteria to identify a candidate midsized cyclic peptide compound — now called Luna18 — for further development.
“Since identifying Luna18, we have improved its binding affinity roughly 9,000-fold without impacting the active conformation. The main chain didn’t change. There was no scale hoping whatsoever, and that’s exactly what we tried to do. So with this proof of concept, we are very confident this research program can proceed,” Hayashi said.
“So what I have shown you is what we achieved through the integration of biotechnology and chemistry. Neither biotech nor chemistry alone can achieve this type of research, [and] that’s what we believe.”