HY809382的临床前表征：一种高效、口服生物利用度高的PRC2 PROTAC，用于治疗淋巴瘤和实体瘤

The Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator that mediates gene silencing through the catalysis of histone H3 lysine 27 trimethylation (H3K27me3). This activity facilitates repression of tumor suppressor genes as well as immune-related transcripts. The core subunits of PRC2 comprise EED, SUZ12, and the catalytic component EZH1 or EZH2. Aberrations of PRC2 components, including mutation and overexpression, have been identified across a range of cancers, highlighting PRC2 as a promising therapeutic target. Although targeting EZH2 has been the primary approach in PRC2 inhibitor development, leading to the FDA approval of Tazemetostat as the first-in-class agent, no PRC2 degraders have yet progressed to clinical trials. The PRC2 degraders provide several potential advantages, such as ​overcoming​ acquired resistance to approved EZH2 inhibitors, ​disrupting​ the stability of the PRC2 complex, and ​enhancing​ efficacy against lymphoma and solid tumors. Herein we disclose HY809382, an orally bioavailable PRC2-targeting PROTAC molecule, as a candidate therapeutic for lymphoma and solid tumors. HY809382 demonstrated degradation of the target protein EED at nanomolar (nM) concentrations, without altering protein levels of known CRBN neo-substrates such as IKZF1/3, GSPT1 and CK1alpha. Proteomic analysis confirmed that HY809382 selectively degraded the target protein EED and its co-complex partner EZH2, demonstrating excellent degradation specificity. The antiproliferative activity of HY809382 surpassed that of approved or clinically investigated small molecule inhibitors targeting PRC2 components. HY809382 exhibited favourable oral pharmacokinetics in preclinical species, with bioavailability (F)≥ 40%. Once-daily oral administration of HY809382 demonstrated significant, dose-dependent tumor growth inhibition in Karpas-422 (DLBCL), G401 (rhabdoid tumor) and 22Rv-1 (prostate cancer) cell-derived xenograft models, outperforming approved or clinically investigated PRC2-related inhibitors. IHC analysis confirmed HY809382-mediated downregulation of key on-target pharmacodynamic markers (e.g., H3K27me3, EED and EZH2) in tumor tissues. A 44-target safety screen indicated a clean off-target profile, and the compound showed low risks of cardiotoxicity and genotoxicity, as supported by hERG inhibition and the mini-Ames tests, respectively. Preliminary non-GLP repeated-dose toxicity studies in mice and cynomolgus monkeys indicated that HY809382 was well tolerated, with estimated therapeutic windows of >95 and >25, respectively. These findings support the potential of HY809382 as a best-in-class PRC2 degrader and warrant its further evaluation in IND-enabling studies.