Design andSynthesisof Type-A ProanthocyanidinDerivatives as JAK2 Activators to Protect against Chemotherapy-InducedMyelosuppression

Abstract 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.