In a study recently published in the journal Nature, scientists from Acus Laboratories GmbH (Acus) characterize a class of novel inhibitors of mitochondrial transcription (IMT).
Altered expression of mitochondrial DNA and downstream activity of oxidative phosphorylation can be critical for cancer cell survival in numerous malignant tumors. In an interdisciplinary effort, small molecule inhibitors of mitochondrial transcription were developed, which induce a strong antitumor effect in in vivo cancer models. IMT thus not only provide a potent tool to study mitochondrial biology, but also harbor high therapeutic potential.
In this study, scientists from Acus validated the mitochondrial DNA polymerase as IMT drug target in live cells and mapped the drug-target binding interface by genetic screens. These pure genetic data were confirmed by a cryo-EM structure of the drug-protein complex. This work highlights the predictive power of the JLP screening technology to identify and validate drug target structures in an entirely unbiased manner. Importantly, this approach reaches amino acid resolution, thus resolving the drug-target binding site.