On June 12, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that Dr. Jacob Stuckey, Senior Scientist at Constellation Pharmaceuticals, gave an oral presentation titled Methods for Kinetic Assessment of High Affinity EZH2 Inhibitors: Identification of a 2nd Generation EZH2i with Improved Biological Activity and Extremely Long Residence Time at the Oxford Global Drug Discovery Summit in Berlin earlier today (Press release, Constellation Pharmaceuticals, JUN 12, 2019, View Source [SID1234537034]).
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Dr. Stuckey described detailed studies conducted by Constellation Pharmaceuticals to characterize molecules from the Company’s second-generation EZH2 inhibitor program. As outlined in Dr. Stuckey’s presentation, potent EZH2 inhibitors present a number of unique challenges for measurement of biochemical potency and residence time. To meet these challenges, the Company developed customized biochemical and binding assays to evaluate these parameters. A key structural modification was identified that bestows prolonged residence time on multiple known EZH2-inhibitor scaffolds. Optimized second-generation EZH2 inhibitors display sub-pM potencies that translate into enhanced cell killing of EZH2-inhibitor-sensitive preclinical models both in vitro and in vivo.
The culmination of the Company’s second-generation EZH2 inhibitor program was the identification of CPI-0209, which reversibly binds to the PRC2 complex with sub-pM binding affinity and a residence time of >3 months. Constellation expects to file an Investigational New Drug (IND) application for CPI-0209 in June 2019.