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.

Keywords: PARP1 inhibitors; antitumor agents; poly (ADP-ribose) polymerase 1.

Fig. 1

Protein poly (ADP-ribosyl)ation reaction

Fig. 2

First-generation PARP1 inhibitor, 3-aminobenzamide (3-AB). A nicotinamide pharmacophore group is shown in red

Fig. 3

Second-generation inhibitors. A nicotinamide pharmacophore group is shown in red

Fig. 4

Structures of third-generation PARP1 inhibitors. A nicotinamide pharmacophore group is shown in red

Fig. 5

Direct cytotoxic effect of PARP1 inhibitors. A – inhibition of PARP1 leads to inactivation of a repair system and preservation of spontaneously occurring single-strand breaks (SSBs), which causes formation of double-strand breaks. B – because of the action of PARP1 inhibitors, PARP1 remains bound to damaged DNA and, thus, cannot dissociate from it and clear the area for PARP1-dependent repair enzymes. C – in the presence of PARP inhibitors, mutant BRCA1 is less accumulated at the DNA damage site, D – when double-strand breaks occur in HR-deficient cells, another NHEJ system is activated. As a result, repair errors occur that can lead to genomic instability and cell death

Fig. 6

The structure of iniparib

Fig. 7

Structural and functional organization of PARP1. The PARP1 structure is composed of three main functional domains: N-terminal DNA-binding domain, internal automodification domain, and C-terminal catalytic domain [108, 109], as well as additional functional sites