Targeting DDX3 with a small molecule inhibitor for lung cancer therapy.

Abstract

Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-β-catenin axis and inhibited non-homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

• Authors: Guus M Bol, Farhad Vesuna, Min Xie, Jing Zeng, Khaled Aziz, Nishant Gandhi, Anne Levine, Ashley Irving, Dorian Korz, Saritha Tantravedi, Marise R Heerma van Voss, Kathleen Gabrielson, Evan A Bordt, Brian M Polster, Leslie Cope, Petra van der Groep, Atul Kondaskar, Michelle A Rudek, Ramachandra S Hosmane, Elsken van der Wall, Paul J van Diest, Phuoc T Tran, Venu Raman
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 7 Issue 5 Pg. 648-69 (May 2015) ISSN: 1757-4684 [Electronic] England
• PMID: 25820276 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• 3,7-dihydro-3,7-bis((4-methoxyphenyl)methyl)-2H-diimidazo(4,5-d:4',5'-f)(1,3)diazepin-2-one
• Antineoplastic Agents
• Azepines
• Imidazoles
• Radiation-Sensitizing Agents
• DDX3X protein, human
• DEAD-box RNA Helicases

Topics

• Animals
• Antineoplastic Agents (isolation & purification, pharmacology)
• Apoptosis
• Azepines (isolation & purification, pharmacology)
• Cell Cycle (drug effects)
• Cell Cycle Checkpoints
• Cell Line
• DEAD-box RNA Helicases (antagonists & inhibitors)
• Humans
• Imidazoles (isolation & purification, pharmacology)
• Lung Neoplasms (drug therapy, radiotherapy)
• Mice, Nude
• Mice, Transgenic
• Radiation-Sensitizing Agents (isolation & purification, pharmacology)