The poly (ADP-ribose) polymerase (PARP) family comprises seventeen DNA-dependent nucleases that are primarily involved in DNA damage repair processes. PARP initiates the base excision repair (BER) pathway by recognizing and binding to single-strand breaks (SSBs) in DNA, thereby completing the repair process [1], [2], [3], [4], [5], [6]. PARP1 has garnered significant attention for its involvement in multiple cellular functions, including cell division, differentiation, apoptosis, and maintaining chromosomal stability [7], [8]. PARP1 knockout animals and cells exhibit heightened sensitivity to alkylating agents. In various diseases, such as breast cancer, melanoma, and lung cancer, PARP1 expression is upregulated [9]. The pivotal role of PARP1 in the DNA damage response makes it a highly promising therapeutic target in cancer treatment [10], [11], [12]. The development of PARP1 inhibitors has achieved significant breakthroughs [13].

Currently, the representative PARP1 inhibitors include Olaparib [14], Rucaparib [15], and Niraparib [16], all of which have been approved by the US FDA (Fig. 1). Among these, Olaparib is the first PARP inhibitor targeting DNA damage response (DDR), which was initially approved by the FDA in December 2014. Research confirms that PARP1 inhibitors block DNA repair through a “synthetic lethality” mechanism, with sensitivity to the inhibitor in BRCA1/2-mutated cancer cells reaching up to 1000 times that of wild-type BRCA cells [17]. However, the application of PARP1 inhibitors faces two major limitations: First, their indication basis (BRCA1/2 mutations) is only observed in a subset of breast and ovarian cancers. Second, their clinical efficacy is often constrained by poor prognosis, tumor heterogeneity, and drug resistance, stemming from their competitive and space-occupying mechanism of action [18], [19].

In recent years, targeted protein degradation (TPD) has garnered significant attention for its ability to degrade proteins, including those previously considered “undruggable” [20], [21]. Within the TPD paradigm, proteolysis-targeting chimeras (PROTACs) and hydrophobic tag (HyT) technologies have turned into the most widely adopted approaches. PROTACs have been developed as diverse PARP1 degraders (Fig. 1). For example, compound 4, the first PARP1 degrader, effectively reduces PARP1 levels in tumor cells through proteasomal degradation, outperforming the original ligand drug, Niraparib, in this regard [22] and consequently inhibiting tumor cell growth. Notably, SK-575 (5), a potent PARP1 degrader derived from Olaparib, exhibits significant degradation effects. However, its anti-proliferative activity against breast cancer cells is comparable to that of Olaparib [23], [24].

While significant progress has been made in the PROTAC-based modification of drugs within the field of medicinal chemistry, HyT technology has garnered relatively less attention. HyT small molecules function as bifunctional targeted protein degraders. Their structure comprises two key elements: a target protein-specific ligand and a hydrophobic tag unit [25]. Currently, the most commonly used hydrophobic tag units are amantadine, benzene rings, and their derivatives [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. Upon engagement of the target protein by the ligand, the hydrophobic tag interacts with the protein surface. This interaction mimics a partially unfolded state, thereby promoting degradation via the proteasome [36], [37], [38] (Fig. 2A). HyT possesses several significant advantages over PROTAC [39], [40]. For instance, it bypasses the need for E3 ligands [41], particularly CRBN ligands, thereby reducing molecular weight and eliminating the teratogenic risk associated with CRBN ligands. This positioning of HyT as a promising technology for TPD [42], [43], [44] is particularly notable.

The design, synthesis, and pharmacological profiling of a HyT-based PARP1 degrader are reported here. By connecting the PARP1 inhibitor Olaparib with a hydrophobic tag through different linkers and introducing a novel low molecular weight hydrophobic tag, the total molecular weight of the compound is reduced. The drug-like properties of the compound are enhanced while maintaining its degradative potency, and efforts are made to degrade the PARP1 protein within various PARP1-positive cancer cell lines. Through systematic structure-activity relationship (SAR) and pharmacological evaluation, compound 11e demonstrated potential as a PARP1 degrader capable of effectively inducing degradation even at low concentrations across multiple cancer cell lines.