Experimental drug CS18 weakens tumors’ defenses and restores sensitivity to treatment
Researchers at Baylor report that CS18, a TopBP1-targeting compound, can weaken tumor survival mechanisms, enhance existing drugs and reverse resistance in preclinical models.
A laboratory-developed molecule dubbed CS18 shows early promise at undermining cancer cells’ ability to survive therapy, according to researchers at Baylor College of Medicine. In cell and animal experiments reported in Science Advances, CS18 disrupted a central regulatory protein in cancer cells, strengthened the effects of existing drugs and reversed resistance in some lung cancer models.
“Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments,” said Dr. Weei-Chin Lin, corresponding author and professor of medicine and molecular and cellular biology at Baylor. The team frames CS18 as a tool to attack that obstacle by targeting a hub that controls multiple survival pathways in tumors.
Targeting a central cancer switch
Rather than aiming at a single pathway, the investigators focused on topoisomerase IIβ-binding protein 1 (TopBP1), and specifically the BRCT7/8 region, which the group describes as interacting with several cancer-promoting regulators. By binding this region, CS18 is reported to blunt the activity of oncogenic factors such as MYC and mutant p53, dampen DNA repair proteins, and boost expression of genes that limit uncontrolled growth.
The compound emerged after computer-guided screening identified a lead molecule (3B6) that was chemically optimized through multiple iterations to produce CS18 as the most active candidate.
Preclinical results across cancer types
Laboratory tests showed CS18 had effects in multiple cancer cell types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia, while showing lower toxicity toward non-cancerous cells. When combined with approved therapies, CS18 enhanced cell killing: it boosted the activity of PARP inhibitors and restored sensitivity to the EGFR inhibitor osimertinib in lung cancer cells that had become resistant.
In animal models, addition of CS18 to treatment regimens led to significant slowing of tumor growth without major weight loss or other overt signs of toxicity, the authors report.
The study’s senior and contributing authors include Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan and Helena Folly-Kossi of Baylor College of Medicine, and Shwu-Jiuan Lin of Taipei Medical University.
Although these findings point to a multi-pronged strategy for overcoming drug resistance, the researchers emphasize that CS18 is at an early, preclinical stage and requires further development and evaluation before any clinical use could be considered.
The work was supported by multiple NIH and Department of Defense grants, a Rivkin Center for Ovarian Cancer Pilot Award and a Taiwan Ministry of Science and Technology grant, and is published in Science Advances (2026).