• MIZ1, a suppressor of the cancer driver MYC
• Mutant p53, which can acquire cancer-promoting functions
• PLK1 and CIP2A, proteins that help cancer cells survive and divide

"All together, these diverse roles position TopBP1-BRCT7/8 as a promising target for intervention," Lin said.

How did the team find CS18?

Researchers screened thousands of chemicals using a combination of computer modeling and laboratory experiments. The search identified a starting compound named 3B6.

They then modified 3B6 and tested numerous versions of the molecule. CS18 emerged as the most effective candidate.

What did the lab tests show?

When CS18 binds to BRCT7/8, the cancer-promoting activities of MYC and mutant p53 decreased, Lin reported. Proteins involved in DNA repair became less active. Cancer cells were more likely to die.

The researchers observed these effects across five cancer cell types:

• Triple-negative breast cancer
• Ovarian cancer
• Lung adenocarcinoma
• Lung squamous cell carcinoma
• Acute myeloid leukemia

CS18 was also less toxic to non-cancerous cells.

The results became particularly notable when the team paired CS18 with cancer drugs already in clinical use. Combining CS18 with PARP inhibitors or osimertinib killed cancer cells more effectively than either treatment used alone.

Could CS18 help where current drugs have failed?

"In the case of lung cancer cells that were already resistant to osimertinib, adding CS18 restored the cells' sensitivity to osimertinib, increasing cancer cell death," Lin said.

In animal models, researchers observed a significant reduction of tumor growth with no major weight loss or other signs of toxicity. These findings are preliminary: CS18 has not yet been tested in humans.

What happens next?

The researchers propose that CS18 warrants further development as a possible component of combination cancer therapies. Such treatments could potentially prevent resistance from emerging or make resistant cancers responsive to therapy again. Clinical development typically takes years, and most experimental compounds never reach approval.

Other Baylor contributors include Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan, and Helena Folly-Kossi. Shwu-Jiuan Lin, at Taipei Medical University, also contributed to the work.

The study received funding from the National Institutes of Health, the Department of Defense, the Rivkin Center for Ovarian Cancer, and Taiwan's Ministry of Science and Technology.