Targeting p27 To 'Let Biology Do The Work' With Stacy Blain, CEO, Concarlo Therapeutics

By Ray Dogum, Chief Editor, Drug Discovery Online

Few scientific careers follow a single straight line. Stacy Blain, Ph.D., followed a single protein.

As a molecular and cell biologist, Blain has spent more than 30 years studying p27, a regulatory protein that sits at the center of cell cycle control. In 2003, Blain published p27 as a target for cancer therapeutics, where she described p27Kip1 as a central regulator that coordinates cyclin E-CDK2 activation with cyclin D-CDK4 accumulation and helps cells exit the cell cycle in response to antigrowth signals.

She also outlined why p27 is a compelling but complex therapeutic target: its protein abundance can predict disease progression, its antiproliferative activity may influence the effectiveness of cell-cycle-dependent therapies, and its levels are controlled after transcription by pathways frequently altered in cancer.

Identifying P27 As A Drug Target

What began as a basic science question during her postdoctoral training at Memorial Sloan Kettering ultimately evolved into Blain starting Concarlo Therapeutics to develop a potential first-in-class cancer therapy.

"I wasn't intending to be an entrepreneur," Blain told me. "I was intending to figure out how this therapeutic target worked. And that led me to drug development."

When Blain arrived at Sloan Kettering, researchers had just discovered p27 and handed her a deceptively simple challenge.

"They had just discovered this brand-new protein called p27, and essentially they handed the protein to me and said, 'Figure out what it does,'" she recalled.

P27, or cyclin-dependent kinase inhibitor 1B (p27Kip1), belongs to a family of intrinsically disordered proteins, meaning it lacks a stable three-dimensional structure until it binds to a target. Those characteristics have historically made proteins like p27 difficult drug targets and have helped keep them largely out of reach of traditional drug discovery approaches.

For Blain, however, that difficulty is what attracted her to the project.

"It was a very unusual protein," she said. "It only folds into a structure when it binds to its targets. So that has eluded traditional drug discovery efforts, so we had to come up with other ways to drug it."

Over the years, her lab uncovered another layer of complexity. P27 can function both as an inhibitor and an activator depending on context, making it what she describes as a cellular "chameleon."

"I liked the fact that it could receive signals, interpret them, and then act on them in one of two different ways," Blain said. "So it was a big challenge, and it has continued to delight for the last 30 years. We're always discovering something new about this."

That work eventually revealed an opportunity to rethink how cancer drugs are designed.

Developing LOCKTAC

Rather than attempting to directly inhibit cancer-driving kinases with traditional small molecules, Concarlo is developing what it calls a LOCKTAC, or lock-and-hold molecular glue. It’s a small molecule that “locks” the tail of p27 into the Cyclin-CDK complex to achieve inhibition. The goal is to stabilize a natural inhibitory interaction that already exists within cells.

"We are sustaining a natural low-affinity interaction into a high-affinity interaction, locking it and holding it and getting the desired outcome," Blain explained. "We're just letting nature do what it normally does, but letting it do it a little bit better."

The approach centers on restoring p27's ability to inhibit CDK2, CDK4, and CDK6, key drivers of cell proliferation. According to Blain, many oncogenic signaling pathways eventually converge on this cell-cycle machinery.

"All of these oncogenic signals are messing up that balance," she said. "Those two are the yin and yang. They need to be in balance to prevent rapid proliferation."

Cancer Treatment Landscape

Current CDK4/6 inhibitors such as Pfizer’s Ibrance (palbociclib), Lilly’s Verzenio (abemaciclib), and Novartis’s Kisqali (ribociclib) have transformed treatment for patients with metastatic breast cancer. But drug resistance remains a persistent challenge.

"The sad reality is that almost 100% of those patients will become resistant with time," Blain said. "The field totally recognizes that you have to inhibit CDK2/4/6. That's what you have to do."

Concarlo's strategy seeks to accomplish that through biology rather than brute-force chemistry.

"What p27 does is it is the natural inhibitor of CDK2/4/6 she said. "So we're going to just get p27 to do its job."

Oral Delivery Strategy

The company's journey has evolved considerably since its early peptide-based programs. While those studies successfully demonstrated the concept in multiple animal models, commercial realities pushed the team toward a more practical solution.

"We said, 'Couldn't we phenocopy what we've seen with this peptide and come up with an oral small molecule?' And we were able to do that," Blain said.

Today, Concarlo is advancing an oral LOCKTAC candidate designed to replicate the biology of the original program while offering the convenience patients and physicians expect from modern cancer therapies.

For Blain, though, the conversation extends beyond any single drug candidate. She believes the future of innovation depends on sustained support for early-stage science, even when the path to commercialization remains uncertain.

"If you want drugs in five years, new drugs, you've got to pay for them now," she said. "We as a society need to fund early-stage innovative work."

After three decades spent following one protein from basic biology to drug development, Blain may be one of the strongest arguments for exactly that kind of long-term investment.