David Heppner, Ph.D., is the Jere Solo Assistant Professor of Medicinal Chemistry at UB. He has led some of the most innovative research in the area of targeted covalent inhibitors (TCIs). That study, published on August 13 in the American Chemical Society’s Journal of Medicinal Chemistry, made one critical discovery. Yet speed may not be the most crucial aspect when it comes to achieving drug development success. Lessons learned from other studies point to a constructive, albeit delicate, balance that TCI design must strike. It is particularly focused on the inactivation efficiency rate and other key parameters.
Heppner’s research team explored 14 distinct advanced molecules. They discovered these to be effective targeted cancer inhibitors (TCIs) for the epidermal growth factor receptor (EGFR), a protein crucial for cell proliferation. When mutations in EGFR are acquired, they can cause the cells to divide uncontrollably, frequently culminating in malignancy. Taken together, these results indicate that improved binding kinetics enhances the potency of TCIs. This increased potency only holds true up to a point. After that, considerations like target selectivity all of a sudden become really important.
Study Findings and Methodology
In the field trial, Heppner and his team ran hundreds of compounds through well-characterized field sites to determine which were effective as TCIs. “Our research suggests that speed isn’t everything when it comes to covalent inhibitor drugs,” stated Heppner. The team found that increasing the rate of inactivation improved effects to the cells. It also underscored the need to more thoughtfully approach other design parameters.
To help TCI development be more precise, researchers suggested a two-step design process. The first stage is to increase the rate of inactivation efficiency of the compound. The second step is to provide a score based on additional criteria. One important aspect is target selectivity, which reflects how well a drug binds to its specific target. This is to ensure that TCI design is targeted for maximum therapeutic efficiency.
The described research included testing of a toxicologically challenging metabolite of a clinically approved molecule as one of the 14 compounds tested. This inclusion provided real learning opportunities to identify where to avoid stumbling blocks in TCI development. What it did was reveal the importance of robust, nonclinical assessments throughout the drug design process.
Team Contributions and Laboratory Insights
Our research team was a passionate group of researchers. It featured Ph.D. students Omobolanle Abiodun, Surbhi Chitnis, and Kishan Patel and undergraduates Abigail Lantry, Kaly Lin, and Emily Ouellette. Their collaborative efforts significantly contributed to the recognition that TCIs could be beneficial to cancer therapy and their mechanisms of action were elucidated.
Heppners lab at the University at Buffalo specializes in human cancer cell culture, providing a perfect fit for the experimental work that took place in their lab. The lab space enabled really creative research approaches to skyrocket this successful study. These discoveries shed light on novel routes to make faster-acting but more selective and precise cancer therapies.
Implications for Future Drug Design
Heppner emphasizes that making informed decisions early in the TCI design process is critical for long-term success. The analysis used to make the discovery underscored how advantageous quick binding is. Yet, it should be done with an eye towards tradeoffs with other important elements of drug efficacy. As such, this study serves to dispel conventional wisdom within the field of medicinal chemistry that emphasizes rapidity of development and delivery above all else.
Beyond TCIs specifically, this research has significant implications turning towards the alternative. It provides a helpful structure for creating future pharmacological approaches in numerous therapeutic categories. Heppner’s findings make a strong case for a more holistic approach to drug design. This new paradigm has the potential to usher in more precise and less toxic treatments for cancer and other diseases with similar underpinnings.