PT  - JOURNAL ARTICLE
AU  - Wai Kwan Tang
AU  - Taivan Odzorig
AU  - Whitney Jin
AU  - Di Xia
TI  - Structural Basis of p97 Inhibition by the Site-Selective Anti-Cancer Compound CB-5083
AID  - 10.1124/mol.118.114256
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.114256
4099  - http://molpharm.aspetjournals.org/content/early/2018/12/21/mol.118.114256.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/12/21/mol.118.114256.full
AB  - Inhibition of p97, a key player in the ubiquitin-proteasome degradation pathway, has been proposed as a treatment for cancer. This concept was nearly realized recently when a potent p97 inhibitor, CB-5083, was developed and demonstrated broad antitumor activity in various tumor models. CB-5083 functions as a competitive inhibitor that binds selectively to the ATP-binding site of the D2 domain, although both the D1 and D2 ATPase sites of p97 are highly similar. Despite its promising anti-cancer activity, CB-5083 failed its Phase I clinical trials due to an unexpected off-target effect, which necessitates further improvement of the inhibitor. In this study, we determined the crystal structure of N-terminal domain-truncated p97 in complex with CB-5083. It provides a structural basis for the specificity of CB-5083 towards the D2 domain, offers an explanation in atomic detail for the mutations that confer resistance to CB-5083, and establishes a foundation for future structure-guided efforts to develop the next generation of p97 inhibitors.