Discovery of RP-37 Analogues as Potent, Selective Irreversible Inhibitors Targeting DNA Polymerase Theta (POLθ)

Zhenwei Wang; Mengyuan Qiu; Deming Liu; Dongyan Gu; Yanzhen Yu; Fengmin Zhang; Rong Sheng

doi:10.1039/d5md00830a

January 1, 2026RSC Medicinal Chemistry

Discovery of RP-37 Analogues as Potent, Selective Irreversible Inhibitors Targeting DNA Polymerase Theta (POLθ)

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Key Points

The research aims to discover potent and selective irreversible inhibitors of DNA polymerase theta for treating BRCA-deficient cancers.
Structure-guided drug design was utilized to develop RP-37 analogues.
The efficacy of the inhibitors was tested in cellular assays to evaluate their potencies against POLθ.
Selectivity was assessed to compare the analogs versus reversible inhibitors.
RP-37 analogues demonstrated significantly higher potency compared to existing reversible POLθ inhibitors.
These analogues showed selective inhibition of DNA polymerase theta, disrupting its function in BRCA-deficient cancer cells.
Improved cellular efficacy was observed, suggesting better theoretical treatment outcomes in target populations.

Implication

Structure-guided discovery identifies potent inhibitors targeting DNA polymerase theta in BRCA-deficient cancers, indicating potential therapeutic advancements.

Abstract

DNA polymerase theta (POLθ) is a promising synthetic lethal target for BRCA-deficient cancers, while reversible POLθ-pol inhibitors exhibit limited cellular efficacy. Here, we report the structure-guided discovery of RP-37 analogue...

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Cite This Study

Wang et al. (2026) studied this question.

synapsesocial.com/papers/696c789ceb60fb80d1396d6c https://doi.org/10.1039/d5md00830a

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Discovery of RP-37 Analogues as Potent, Selective Irreversible Inhibitors Targeting DNA Polymerase Theta (POLθ)

Key Points

Implication

Abstract

Discussion

Cite This Study

Discovery of RP-37 Analogues as Potent, Selective Irreversible Inhibitors Targeting DNA Polymerase Theta (POLθ)

Key Points

Implication

Abstract

Discussion

Cite This Study

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