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Updated: Jan 7, 2026
Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source
Published on: May 29, 2021
Discovery of 1-(arylacetyl)-2-phenyl-pyrrolidine Derivatives as Novel POLθ-pol Inhibitors via Structure-Based Virtual
Wenlin Fan1, Mengyuan Qiu2, Zhenwei Wang1,3,4
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Abstract:
DNA polymerase theta (POLθ) has been regarded as a promising therapeutic target for the treatment of BRCA-deficient tumors. In this study, 1-(arylacetyl)-2-phenyl-pyrrolidine derivative VS-13 was identified as a POLθ-pol inhibitor hit with an IC50 value of 1.47 μM through virtual screening. The followed similarity research obtained a more potent analogue SS-5, which was hybridized with RP-6685 to get 1-(phenylacetyl)-2-phenyl-pyrrolidine derivative F-1. It showed potent POLθ inhibitory activity with an IC50 value of 170 nM, and good anti-proliferative activity against BRCA2-deficient DLD1 and HCT116 cell lines, with IC50 values of 4.39 μM and 4.79 μM, respectively. Further MD simulations and interaction analysis disclosed the possible binding mode of F-1 with POLθ-pol.
