Discovery of 1-(arylacetyl)-2-phenyl-pyrrolidine Derivatives as Novel POLθ-pol Inhibitors via Structure-Based Virtual Screening and Fragment Fusion.

Authors

Wenlin Fan, Mengyuan Qiu, Zhenwei Wang, Geng Chen, Yanzhen Yu, Rong Sheng

Published in

Drug development research. Volume 87. Issue 1. Pages e70216.

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.

PMID:
41459625
Bibliographic data and abstract were imported from PubMed on 29 Dec 2025.

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