Design and Synthesis of Type-A Proanthocyanidin Derivatives as JAK2 Activators to Protect against Chemotherapy-Induced Myelosuppression
Jianqiang Qian, Rong Wang, Weihua Lei, Jingyi Lai, You Li, Wei Shi, Mingshi Pan, Jiamin Cui, Zihao Wang, Xiaoqi Zhang, Wencai Ye, Fei Xiong, Xiaolong Hu, Hao WangAbstract
Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Proanthocyanidin A1 (1) from peanut skin is a JAK2 activator to alleviate CIM, but the SAR and drug-like properties of Type-A proanthocyanidins remain unclear. Here, a series of Type-A proanthocyanidin derivatives (5–35) were designed, synthesized, and evaluated for JAK2 activation, leading to the identification of compound 32 as the most potent activator (EC50 = 64 nM). Target-binding assays demonstrated that 32 directly bound JAK2 and displayed preferential affinity for the JH2 pseudokinase domain over the JH1 catalytic domain, indicating a potential JH2-mediated activation mechanism. In primary BMHSCs, 32 activated the JAK2/STAT3 pathway and alleviated carboplatin-induced damage. Consistently, oral administration of 32 at 50 mg/kg activated JAK2/STAT3 signaling in vivo and promoted hematopoietic recovery in CIM mice, with favorable bioavailability and acceptable preliminary safety. These findings identify 32 as a promising orally available JAK2 activator for CIM treatment.