Poly (ADP-ribose) polymerase inhibitors (PARPi) are crucial for treating BRCA-deficient cancers; however, therapeutic efficacy is limited due to resistance mechanisms and off-target effects, such as chronic anemia.
In a previous study, we identified a 2-benzylidene substituted dihydrobenzofuran-7-carboxamide (DHBF-7-CONH₂) scaffold as a potent PARP1 inhibitor. In this study, we aimed to enhance the cellular potency and solubility of the DHBF-7-CONH₂ scaffold by exploring its 2-thienylidene substituted bioisostere. To achieve this, we utilized (Z)-5-((7-carbamoyl-3-oxobenzofuran-2(3H)-ylidene)methyl)thiophene-2-carboxylic acid as lead compound 2. The modified lead compound was further functionalized by attaching various substituted amines to the adenosine binding pocket (ABP) region of PARP1, producing a series of compounds with IC₅₀values ranging from 17 nM to 640 nM.
Molecular docking simulations revealed key interactions between the compounds and the active site of PARP1, helping to elucidate their structure-activity relationship (SAR). We tested the cellular inhibition of PARP activity in HEK293 cell lines and identified three promising compounds (compounds 11, 13 and 15) which exhibited robust inhibition at 1 μM and 10 μM concentrations. Additionally, we evaluated the in vitro ADME properties of these compounds, with a focus on aqueous solubility and metabolic stability. Top compounds were then tested for their interaction with multidrug resistance ABC transporters (P-glycoprotein (P-gp) and ABCG2). While some of the compounds demonstrated favorable solubility, further optimization is required to improve metabolic stability and achieve more efficacy.

Murakami Megumi

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