Read the latest in development of a potent and selective Polθ inhibitor, laying the groundwork for combination strategies to treat HR-deficient cancers from NIS, Repare Therapeutics, Lunenfeld-Tanenbaum Research Institute, Paraza Pharma Inc, Piramal Pharma Ltd, and Sloan Kettering Institute.
We are proud of our contributions to the development of a potent and selective Polθ inhibitor, laying the groundwork for combination strategies to treat HR-deficient cancers.
In “The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor“, NanoImaging Services collaborated with scientists from Repare Therapeutics, Lunenfeld-Tanenbaum Research Institute, Paraza Pharma Inc, Piramal Pharma Ltd, and Sloan Kettering Institute to aid in the discovery of RP-2119, a Polθ ATPase Inhibitor shown to increase the effectiveness of PARP inhibitors for the treatment of select cancers.
Our team used cryo-EM to solve the structures of inhibitors bound to Polθ at resolutions ranging from 2.7 Å to 2.9 Å. These high-resolution structures elucidated the binding site and enabled structure-based drug design to improve both potency and ADME properties.
These findings help advance combination therapies that exploit synthetic lethality in cancer cells while maintaining tolerability.
The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor
Philippe Mochirian, Robert Papp, Marie-Claude Mathieu, Gino B. Ferraro, Evelyne Dietrich, Bingcan Liu, David Bendahan, Alexander L. Perryman, Simon Surprenant, Sara Fournier, Bita Lotfollahzadeh Barzili, Alexanne Bonneau-Fortin, Shou Yun Yin, Marie-Eve Leclaire, Charmi Patel, Hugo Poirier, Sai Save, Yann Mathieu, Nicolas Morin, Claude Godbout, Helen E. Burston, Karl E. Zahn, Mohamed A. Attia, Thomas Pinter, Francis Barabé, Paranjay Parikh, Chandresh Jagani, Gyunghoon Kang, Giovanna Scapin, Yael Mamane, Agnel Sfeir, Pavel Mader, Frank Sicheri, Michal Zimmermann, Anne Roulston, Stephen J. Morris, W. Cameron Black, and Michel Gallant
Journal of Medicinal Chemistry Article ASAP
DOI: 10.1021/acs.jmedchem.5c02103
