BY101921: Restoring interferon signaling and anti-tumor immunity through PARP7 inhibition.

3123 Background: PARP7( TIPARP), a member of monoPARP family, catalyzes ADP-ribose transfer to specific amino acids within itself and other substrate proteins, utilizing nicotinamide adenine dinucleotide (NAD + ) as substrate. It plays a vital role in various biological processes such as gene expression, protein degradation, and cellular stress response. PARP7 amplification has been observed in various cancers, including squamous cell carcinoma, ovarian cancer, breast cancer, and pancreatic ductal adenocarcinoma. Over expression of PARP7 correlates with reduced survival in squamous cell carcinoma. PARP7's MARylation of α-tubulin induces microtubule instability, promoting proliferation and migration of ovarian cancer cells. As a negative regulator of tumor cell nucleic acid sensing, PARP7 inhibits TBK1 through. This, in turn, hampers the cGAS-STING signal pathway and downregulates the type Ⅰ interferon expression. BY101921, developed by Chengdu Baiyu Pharmaceutical, is a highly selective PARP7 inhibitor demonstrating significant anti-tumor effect in vitro and in vivo, both alone and in combination with anti-PD-1. Methods: Enzymatic evaluation was conducted on BY101921 to assess its selectivity among major PARP family members. PK studies were investigated in both mouse and dog species. The anti-tumor activity of BY101921, both as a monotherapy and in combo with anti-PD-1, was investigated in NCI-H1373 and CT26 tumor-bearing mice, respectively. In terms of anti-tumor mechanism, pSTAT1, IFN-β and CXCL10 levels were analyzed in RAW264.7 cells and CT26 tumor-bearing tissues. In addition, the effect of BY101921 on the type Ⅰ interferon signaling pathway was systematically evaluated. Results: BY101921 demonstrated outstanding selectivity as a PARP7 inhibitor, displaying limited off-target effects on PARP1/2, reducing the risk of systemic toxicity, especially hematologic effects. In mice and dogs, BY101921 revealed favorable PK characteristics following oral administration. In vivo, BY101921 exhibited potent inhibition of tumor growth as a monotherapy, and its combination with anti-PD-1 further enhanced its anti-tumor efficacy, with excellent tolerability in animals. Mechanism of action studies showed that BY101921 generated an anti-tumor immune response by upregulating pSTAT1 levels and promoting the secretion of IFN-β and CXCL10, thereby restoring the type Ⅰ interferon signaling pathway. Conclusions: BY101921, a potent and selective PARP7 inhibitor, demonstrates significant anti-tumor efficacy both as a monotherapy and in combo with anti-PD-1, while maintaining excellent tolerability in animal models. With favorable drug-like properties and a promising safety profile, BY101921 holds potential as an enhanced therapeutic option for cancer patients. At present, clinical studies investigating BY101921 as a single agent and in combo with anti-PD-1 are in the recruitment phase.