A study led by scientist Andrew Novak and published last November in the prestigious Journal of Medicinal Chemistry explored a new therapeutic approach targeting malignant cell proliferation.
Under the title Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation, a new drug against malignant cells was found using methods such as High Throughput Screening (HTS) and Caco-2 permeability assay with CacoReady plates.
The challenge of nucleotide synthetase inhibitors
Nucleotides are essential for DNA and RNA synthesis, as well as for phospholipid and protein production. While cells can recycle nucleotides, de novo synthesis pathways play a crucial role in rapidly proliferating cells, including malignant and immune cells. One key molecule, cytidine 5′-triphosphate (CTP), has been associated with uncontrolled cell proliferation.
Although previous pyrimidine synthesis inhibitors have been explored as therapeutic agents, their clinical application has been limited by toxicity and low selectivity.
Targeted approach with oral availability
This study focused on CTP Synthetase 1 (CTPS1), an enzyme critical for synthesizing CTP at the end of the metabolic pathway and which plays a critical role in the proliferation of lymphoid cells. The researchers aimed to identify selective inhibitors while ensuring sufficient intestinal permeability for oral administration.
To achieve this, they:
- Screened over 240,000 molecules using high-throughput screening (HTS).
- Assessed intestinal permeability of selected compounds using CacoReady plates.
- Conducted selectivity assays via mass spectrometry.
- Evaluated the in vivo efficacy of the most promising candidate in a mouse CIA model.
Conclusions of the article
After all steps, the study identified a new series of acetamides as potent CTPS1 inhibitors, with the lead compound demonstrating promising anti-inflammatory activity in vivo. Optimization efforts are ongoing to further refine the compound’s potency and selectivity.
Read full article: Novak A, Laughton D, Lane R, Blackham E, Thomas J, Chatzopoulou E, et al. Discovery and optimization of potent and orally available CTP synthetase inhibitors for use in treatment of diseases driven by aberrant immune cell proliferation. J Med Chem. 2022;65(24):16640-16650. doi:10.1021/acs.jmedchem.2c01446.
