Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance

Abstract

Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.

YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors

“…IC 50 values of PARPs were obtained from histone-based (a) or biotinylated NAD + -based (b) luminescence assays. c Data from ref …”

Discovery of Quinazoline-2,4(1H,3H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis

“…Especially, it was observed that RBN2397 displayed an enhanced antitumor activity when dosing to the mice bearing PARP-1/2 KO CT-26 tumor cells . Furthermore, thioparib having PARP-1/2/7 inhibitory activity demonstrated high in vivo antitumor activity as well . Therefore, Cpd36 that embraced strong inhibition toward PARP-1/2/7 simultaneously was expected to produce beneficial antitumor effects.…”

“…42 Furthermore, thioparib having PARP-1/2/7 inhibitory activity demonstrated high in vivo antitumor activity as well. 40 Therefore, Cpd36 that embraced strong inhibition toward PARP-1/2/7 simultaneously was expected to produce beneficial antitumor effects.…”

“…This rational combination treatment is potentially able to produce synergistic effects, boosting the effectiveness of both PARP-1/2 inhibitors and the PD1/PD-L1 blockers, and to expand their utilization against multiple tumors. Very recently, thioparib and YCH1899 (Figure ) were disclosed as a new-generation PARP inhibitor which exhibited strong inhibition toward multiple PARP isoforms, including PARP-1, PARP-2, and PARP-7. , PARP-7 is considered as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP-7 could promote type I interferon (IFN) signaling responses to nucleic acids in a TBK1-dependent manner in tumor models, which resulted in the inhibition of cell proliferation and the immune system activation, thus leading to tumor regression .…”

“…Currently, PARP-7 selective inhibitors have drawn a lot of attention, and RBN2397 has entered phase II clinical trial . In addition, it was suggested that the hematological toxicity of known PARP-1/2 inhibitors was possibly associated with PARP-2 inhibition. , Thus, many efforts have been put on PARP-1 selective inhibitors, and two candidates (AZD5305, AZD9574) have advanced into the clinical trial. , It was also conjectured that dual inhibition of PARP-1 and PARP-7 was a promising strategy for antitumor immunotherapy . Altogether, exploring novel PARP inhibitors with distinct pharmacology, including PARP-1 selective inhibitor, PARP-7 selective inhibitor, and multi-isoforms of PARP inhibitors to improve the clinical utilization is expected to have great potential and deserved to be investigated extensively.…”