Published today in Nature Communications, a panel of CYP3A4 inhibitors from the lab of Taosheng Chen, PhD, PMP, St. Jude Department of Chemical Biology & Therapeutics, lays the groundwork for selective cytochrome P450 inhibition.
(MEMPHIS, Tenn. – April 10, 2025) Cytochrome P450 (CYP) proteins are responsible for breaking down more than 80% of all Food and Drug Administration (FDA) approved drugs, reducing their effectiveness. However, how to prevent CYPs from doing this without off-target effects has puzzled researchers until now. Scientists at St. Jude Children’s Research Hospital have designed new drug frameworks that selectively target CYP3A4, one of the most critical CYP proteins. Structural insights from this work offer a roadmap for future drug developers to better evaluate drug interactions and selectively target CYP proteins. The findings were published today in Nature Communications.
CYP3A4 breaks down drugs that treat various health conditions, including the anti-cancer agent paclitaxel and COVID-19 therapeutic nirmatrelvir. CYP3A4 inhibitors are commonly co-administered to reduce CYP3A4’s effect. This includes ritonavir, which is combined with nirmatrelvir in Paxlovid for mild COVID-19 treatment. However, such CYP3A4 inhibitors often affect the similar but distinct CYP3A5 due to the two proteins’ shared features, such as large and promiscuous binding sites, in addition to other unintended CYPs.
If not accounted for, the unintended inhibition of CYP3A5 and other CYPs can have drastic effects. “When a nonselective CYP3A inhibitor is used to maintain the efficacy of a CYP3A4-metabolized drug, the unnecessary inhibition of other CYPs will lead to dangerously elevated plasma levels of drugs metabolized by the unintended CYPs,” said corresponding author , St. Jude .
To address the need for more selective CYP3A4 inhibitors, the researchers performed high-throughput screening to trim 9299 candidate compounds down to a panel of three inhibitor scaffolds that achieved selective and potent CYP3A4 inhibition.
Structural studies reveal key loop within binding pocket
The researchers used X-ray crystallography to investigate the mechanism behind their selectivity. A structural comparison between CYP3A4 and CYP3A5 revealed a loop at the end of the CYP3A5 protein (its C-terminus), which acts as a physical barrier.
“There is a narrower binding pocket for CYP3A5, which prevents CYP3A4 inhibitors from binding,” said Chen.
Using this information, the researchers optimized the inhibitor structure to maximize selectivity and potency. One of the optimized inhibitors, SCM-08, exhibited a 46-fold difference in CYP3A4 inhibition versus CYP3A5 and avoids other CYP proteins involved in off-target binding of existing CYP inhibitors.
SCM-08 may serve as a key launching point to design even more selective CYP3A4 inhibitors. “Our goal is to improve the potency but maintain the selectivity of our CYP3A4-selective inhibitors,” Chen said. “These compounds are the starting points to achieve that, which is now feasible because of the structural basis of selectivity we have uncovered.”
Authors and funding
The study’s co-first authors are Jingheng Wang, Stanley Nithianantham, Sergio Chai and Young-Hwan Jung, St. Jude. The study’s other authors are Lei Yang, Han Wee Ong, Yong Li, Yifan Zhang and Darcie Miller, St. Jude.
The study was supported by grants from the National Institute of General Medical Sciences (R35GM118041) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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