South Korean researchers have developed a novel anticancer approach capable of selectively turning off specific cellular "switches" that drive tumor growth, even within the complex signaling environment of human cells.
The technique is expected to minimize off-target side effects associated with conventional drugs that destroy entire proteins, offering a significantly more precise treatment paradigm.
A joint research team led by Professors Kwon Taek-gyu (College of Medicine) and Park Kwang-soo (College of Pharmacy) at Keimyung University, alongside Professor Shin Dong-hyuk (Department of Biological Sciences) at Yonsei University, announced on September 8 the development of "bioPhosTAC"—a platform technology designed to selectively remove specific phosphorylation signals from target proteins.
The findings were published in the international multidisciplinary journal Advanced Science (Impact Factor 14.1). Keimyung University researchers Seo Seung-eon and Woo Seon-min, along with Yonsei University researcher Choi Min-hyung, participated as co-first authors.
Erasing the Oncogenic Signals That Fuel Cancer
Cells regulate growth and division through protein phosphorylation—a process in which a phosphate group acts as a molecular switch to alter protein function. When these switches malfunction, uncontrolled cellular growth can lead to cancer.
Conventional targeted anticancer drugs typically work by broadly inhibiting protein kinases, the enzymes responsible for attaching these phosphate switches. However, because these kinases also regulate vital functions in healthy cells, broad inhibition frequently triggers off-target toxicity.
Rather than blocking entire kinase enzymes, the research team employed a "proximity-induced" strategy. By bringing a dephosphorylating enzyme (phosphatase) directly to the malfunctioning protein, bioPhosTAC selectively strips away only the problematic phosphate switch.
An AI-Designed Molecule with a Dual-Action Structure
Utilizing artificial intelligence-based protein engineering, the team constructed bioPhosTAC as a bifunctional therapeutic molecule featuring two distinct binding domains. One domain binds specifically to the cancer-associated target protein (OTUB1), while the other engages a designated phosphatase (SHP2), pulling the two proteins into close physical proximity.
In experimental models, conventional kinase inhibitors (such as Src kinase inhibitors) broadly reduced phosphorylation across numerous non-target proteins simultaneously. In contrast, bioPhosTAC precisely removed only the specific phosphate switch at the Y26 site on OTUB1, leaving surrounding normal proteins unaffected. This targeted action successfully shut down the Raptor-mTORC1 signaling pathway—a core engine driving cancer cell proliferation.
Targeted Delivery and Future Outlook
To further enhance cancer-cell selectivity, the researchers conjugated bioPhosTAC with a tumor-targeting peptide that recognizes KKLC-1, a surface marker expressed on cancer cells. This design allowed the therapeutic molecule to selectively penetrate and concentrate within tumor tissues.
In vitro and in vivo animal studies demonstrated that the bioPhosTAC platform successfully induced selective cancer cell death and significantly suppressed tumor growth.
Experts view the technology as a major breakthrough that advances beyond existing Targeted Protein Degradation (TPD) therapies. Rather than destroying an entire functional protein, bioPhosTAC enables signal-level precision. Furthermore, its modular architecture allows straightforward adaptation to target various other disease-related proteins.
"While existing drugs have focused on identifying which kinase to inhibit, bioPhosTAC represents a fundamental paradigm shift focused on selecting which specific phosphorylation signal to remove," said Professor Kwon Taek-gyu. "This approach holds immense potential as a next-generation precision strategy that maximizes therapeutic efficacy while reducing side effects."
Professors Park Kwang-soo and Shin Dong-hyuk added, "This platform establishes a new frontier in precision medicine, moving beyond the brute-force elimination of whole proteins to finely tune individual cellular signals."
