DK-AT390HCl: A novel first-in-class small-molecule candidate demonstrating antitumor activity in an animal model of colorectal cancer

Toward a novel therapy for colorectal cancer

Damian Kułaga, PhD, Eng., from the Faculty of Chemical Engineering and Technology at the Tadeusz Kościuszko Cracow University of Technology, is working on a novel drug for colorectal cancer. The therapy he is developing represents an innovative approach to treating this type of cancer. The compound under investigation acts distinctly from current chemotherapeutics or routinely used targeted therapies, as it targets transcription factors within cancer cells - proteins that assist cells in "reading" genes. This acts as a molecular key, locking or unlocking access to the instructions encoded within genes. The research is funded under the European Funds for a Modern Economy 2021–2027 (FENG) program via a Proof of Concept grant awarded by the Foundation for Polish Science.

Colorectal cancer is the third most common cancer worldwide, accounting for 11% of all cancer diagnoses. More than half of these cases occur in high-income countries. In Europe, colorectal cancer ranks as the second most prevalent cancer, with approximately 500,000 residents diagnosed each year. The steady increase in incidence is driven by an aging population (as it primarily affects individuals over the age of 50) as well as poor diet and lifestyle factors. Risk factors for colorectal cancer include overweight, obesity, a diet high in red meat and refined grains, smoking, and alcohol consumption. Currently available treatment modalities for colorectal cancer include surgical intervention, radiotherapy, conventional chemotherapy, molecularly targeted therapies, and immunotherapy. Unfortunately, the efficacy of these methods remains insufficient, driving the ongoing search for novel ways to overcome colorectal cancer. One such innovative approach is currently being evaluated by Dr. Damian Kułaga.

"Within a project funded by the National Centre for Research and Development under the LIDER XII program - focused on developing anticancer compounds targeting breast cancer, which I am currently leading - we generated a pool of compounds that did not perform entirely as anticipated for that specific target. After establishing a collaboration with Dr. Izabela Siemińska from the University of Agriculture in Krakow, we attempted to evaluate these compounds in the context of colorectal cancer. It turned out that one of them, designated DK-AT390HCl, exhibited exceptionally high cytotoxicity against colorectal cancer cell lines (both human and murine), while remaining non-toxic to healthy cells. Additional assays combined with an analysis of current scientific literature led to an initial hypothesis that our compound might act as an inhibitor of the transcription factor known as FOXM1," reports Dr. Kułaga.

The transcription factor FOXM1 is a key regulatory protein that triggers the expression of specific genes in cancer cells. Consequently, inhibiting FOXM1 means these genes become inactive, which can arrest tumor progression. Molecular studies already conducted by Dr. Kułaga's team demonstrate that the compound DK-AT390HCl indeed inhibits FOXM1 transcription factor activity at both the protein and gene levels. Under the Proof of Concept project, further studies are planned to explore this molecule and its potential in combating colorectal cancer.

"The most critical phase will involve mouse studies. Before reaching that stage, however, we will perform structural assays to determine how our molecule binds to the transcription factor, screen the compound for activity against nearly 500 kinases, and execute studies to establish the maximum tolerated dose in mice. Next, we will administer the substance to mice with orthotopically induced colorectal tumors generated by introducing cancer cells into the large intestine. We will evaluate whether our compound reduces tumor mass and volume, as well as whether it inhibits metastasis if the tumor spreads. After a specified period of therapy, we will harvest tumor tissues for histopathological examination to verify whether FOXM1 inhibition actually occurred as a result of the treatment," explains the researcher, who has already signed a letter of intent with a pharmaceutical company. "Through our partnership with an industry representative, we will know what steps must be taken next to successfully commercialize our molecule so that it can eventually reach patients - in its current form or perhaps as an optimized analog," concludes Dr. Damian Kułaga.

Damian Kułaga, PhD, Eng., is a medicinal chemist. He earned his Bachelor's and Master's degrees in fine chemical technology at the Tadeusz Kościuszko Cracow University of Technology, where he also obtained his PhD in chemical engineering. He is the author of peer-reviewed publications and conference presentations, a co-inventor of three national patents—including one as lead author—a co-inventor on five additional patent applications, and a co-developer of two industrial implementations. He has served as principal investigator on four computational grants and an NCBR LIDER XII project focused on targeted therapeutics for aggressive breast cancer. He has completed three scientific internships: at the pharmaceutical company Selvita, the Maj Institute of Pharmacology of the Polish Academy of Sciences, and Sapienza University of Rome. He is a recipient of the R&D Impact Award. Dr. Kułaga's primary research interests focus on interdisciplinary studies at the intersection of organic and medicinal chemistry, dedicated to discovering novel therapeutics for lifestyle diseases.