Researchers identify new compounds for selective SERCA 1 inhibition in metastatic cancer without cardiac side effects

Korean researchers developed new substances that inhibit a target protein for treating metastatic thyroid cancer while reducing heart-related side effects, Severance Hospital said on Monday. 

A research team led by Professor Park Ki-cheong of the Department of Surgery at Yonsei University College of Medicine and Professor Kim Seok-mo of the Department of Surgery at the Thyroid Cancer Center, Gangnam Severance Hospital, announced on Monday that they have developed new substances that inhibit the growth of cancer cells by blocking the SERCA protein, while also reducing the side effects related to heart disease. Their findings are based on a study of cancer cell tissues from patients with metastatic papillary thyroid cancer who are resistant to existing anti-cancer drugs.

The findings were published in the latest issue of the international journal British Journal of Pharmacology (IF 6.8).

Metastasized cancer cells are often prone to developing resistance to existing anti-cancer drugs. Inhibiting SERCA proteins has emerged as a promising approach in treating metastatic cancer, as studies have shown that blocking SERCA function can enhance the effectiveness of anti-cancer therapies. However, the development of SERCA inhibitors was previously halted due to their association with cardiac side effects.

The SERCA protein consists of three subtypes—SERCA 1, 2, and 3—with SERCA 2 playing a key role in the contraction and relaxation of heart muscles. Previously developed SERCA inhibitors targeted the protein without differentiating between its subtypes, which made it impossible to avoid heart-related side effects.

The researchers developed two new selective inhibitors, CKP1 and CKP2, designed to target SERCA 1 while sparing SERCA 2, which is crucial for heart function. SERCA 1 has been identified as a key factor in increasing resistance to cancer drugs. The drug development was carried out in collaboration with CKP Therapeutics, a Boston-based company.

The research team compared the effectiveness of the two new drugs with existing standard anti-cancer treatments, sorafenib and lenvatinib. They isolated resistant metastatic cancer cells from the tissues of patients who had undergone treatment with these standard drugs and subsequently experienced metastasis. Using these cells, they developed a mouse model characterized by elevated levels of the SERCA 1 protein.

While sorafenib and lenvatinib showed no anti-cancer effects in their respective treatment groups, the combination of CKP1 or CKP2 with sorafenib or lenvatinib significantly inhibited tumor growth without causing any cardiac side effects.

To further evaluate potential heart disease side effects, normal mice were treated with the existing SERCA inhibitor, thapsigargin, as well as the two new compounds, CKP1 and CKP2. The results showed that 30 percent of the mice treated with thapsigargin died, whereas no deaths occurred in the groups treated with CKP1 or CKP2.

The team stated that these results indicate CKP1 and CKP2 selectively inhibit the function of SERCA 1 while leaving SERCA 2 unaffected, thereby eliminating the risk of heart disease side effects.

"Through this study, we have developed a drug that can not only treat metastatic cancer resistant to existing anti-cancer drugs, but also minimize the risk of heart disease side effects," said Professor Kim. 

“We will continue to develop therapies for the treatment of intractable cancers,” said Professor Park, adding, “Since the results of this research have been patented both domestically and internationally, they will serve as a foundation for further research, clinical studies, and new drug development.”