Optimization of a Second-Generation, Highly Selective Polθ/PARP1 Dual Inhibitor with Improved Pharmacokinetics and Potent Activity against HR-Deficient Tumors
Luyu Ma, Mingzhe Zhong, Yingxuan Chang, Mingjin Luo, Xinyan Liu, Xiaofan Ge, Sitian Xu, Yun Zhang, Ziye Liu, Hua Xiang, Guoshun LuoAbstract
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.