PhAs-LHP

PhAs-LHP is a peptide-drug conjugate (PDC) consisting of the arsenic-based compound phenylarsine oxide (PAO) covalently linked to the leukemia-homing peptide (LHP) CAYHRLRRC. Developed to overcome the systemic toxicity and low specificity of arsenic trioxide (ATO) in solid tumors, PhAs-LHP specifically targets the macropinocytosis pathway, which is significantly upregulated in KRAS-mutant cancers such as pancreatic ductal adenocarcinoma. By utilizing the RLRR penetrating motif within the LHP ligand, the drug achieves enhanced intracellular arsenic accumulation. Once inside the cell, it induces G2/M cell cycle arrest and apoptosis, primarily through the downregulation of S-phase kinase-associated protein 2 (Skp2). Preclinical studies have demonstrated that PhAs-LHP is approximately ten times more potent than ATO in vitro and significantly enhances the efficacy of gemcitabine in vivo while reducing arsenic distribution to the heart and liver, thereby potentially mitigating cardiotoxicity and hepatotoxicity.

Other names

peptide-linked arsenic compoundphenylarsine-LHPphenylarsine oxide-CAYHRLRRC conjugate