Optimization of a Second-Generation, Highly Selective Polθ/PARP1 Dual Inhibitor with Improved Pharmacokinetics and...

Dual inhibition of Polθ and PARP1 represents a promising precision therapy strategy for HR-deficient tumors. While our first-generation Polθ/PARP1 dual inhibitor 4 provided proof-of-concept, its further development was hampered by poor selectivity over PARP2 and metabolic instability. Herein, we describe a structure-guided optimization that pioneers the integration of PARP1-selective pharmacophores. This effort culminated in the discovery of compound PP-048 (23), a second-generation dual inhibitor with single-digit nanomolar potency against Polθ and PARP1 (IC50 = 4.9 nM and 6.8 nM, respectively) and >226-fold selectivity over PARP2, PARP3, PARP5a/b, and PARP7. Notably, PP-048 displayed markedly improved hepatic stability and favorable oral systemic exposure. In an MDA-MB-436 xenograft model, PP-048 (10 mg/kg) achieved marked tumor growth inhibition (TGI = 91%) without eliciting the hematologic toxicity associated with PARP2 inhibition. To our knowledge, PP-048 represents the first reported PARP1-isoform-selective dual inhibitor, establishing a strategic foundation for development of this emerging class of inhibitors.