If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Molecule Stymies An Old Cancer Drug Target In A New Way

Tests in cells suggest binding to a groove on a retinoid X receptor, rather than a pocket, offers new therapeutic possibilities

by Carmen Drahl
June 9, 2014 | A version of this story appeared in Volume 92, Issue 23

Just about every drug or drug candidate that targets retinoid X receptor α (RXRα), a transcription factor protein implicated in cancer and other diseases, binds in the same pocket as its natural ligands. Medicinal chemists would like more options because retinoid X drugs can have side effects such as liver swelling. In relatives of RXRα, such as the estrogen receptor, researchers have targeted a surface groove where peptides and proteins that coregulate the receptor bind. Xiao-kun Zhang of the Sanford-Burnham Medical Research Institute in La Jolla, Calif., and China’s Xiamen University surmised it might be possible to use that strategy with RXRα. Zhang, a coinventor of the RXR-targeted lymphoma treatment bexarotene, teamed with Ying Su and coworkers to computationally screen 200,000 compounds for possible RXRα blockers aimed at the coregulator binding site. After in vitro tests, they found compound 23, which binds only to the coregulator binding groove, not to the ligand binding site (ACS Med. Chem. Lett. 2014, DOI: 10.1021/ml5000405). The molecule stymied RXRα’s interaction with the cancer-linked kinase enzyme phosphoinositide-3-kinase, which Zhang’s team thinks triggered cancer cell death in their tests. The group is filing a patent application on the technology.


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.