PARP1 Inhibitors: Antitumor Drug Design

Abstract

The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1–2 million molecules per cell) serving as a “sensor” for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

“…PARP1/2 inhibitors improve the health of mice on a HFD (Cerutti et al, 2014). Although, their toxicity may preclude them from use in chronic diseases, there are others with fewer side effects in development (Malyuchenko et al, 2015). …”

Emissive Synthetic Cofactors: A Highly Responsive NAD+ Analogue Reveals Biomolecular Recognition Features

“…Hence, PARP1 functions as a regulatory key enzyme, which is involved in DNA damage response, metabolic regulation and transcriptional activation processes, among others . Association with severe diseases makes PARP1 an attractive therapeutic target, which is driving the development of new inhibitors and treatment of breast, prostate, and ovarian cancer, among others …”

“…To restore cellular NAD + levels and thus counteract detrimental pathways, inhibition of NAD + ‐consuming enzymes, most notably poly(ADP‐ribose)polymerase 1 (PARP1) and CD38/CD157, has shown promise . The significance of NAD + ‐mediated processes necessitates the development of new tools and probes to facilitate biophysical analyses and the fabrication of effective discovery assays.…”

DNA repair in trinucleotide repeat ataxias

“…Mutated of TDP1 gene results in SCA with axonal neuropathy, which is characterized by cerebellar ataxia, peripheral neuropathy, hypercholesterolaemia and hypoalbuminaemia [40]. The central role of XRCC1 in SSB repair and availability of PARP1 inhibitor make PARP1 a promising novel target for treating ataxia with repeat expansion tracts [89]. Recently, cerebellar ataxia due to mutated XRCC1 gene was reported in three unrelated patients [84,85].…”

“…In a Xrcc1 deficient mouse model, persistence of DNA strand breaks lead to drastic loss of cerebellum interneurons [88]. The central role of XRCC1 in SSB repair and availability of PARP1 inhibitor make PARP1 a promising novel target for treating ataxia with repeat expansion tracts [89].…”