A Prostate-Specific Membrane Antigen-Targeting Small Molecule–Drug Conjugate Strategy to Overcome the Hematological Toxicity of Olaparib

PARP
inhibitors have gained attention in the treatment
of metastatic
castration-resistant prostate cancer, but approximately half of patients
have to abort treatment due to severe hematological toxicity. Herein,
we proposed a prostate-specific membrane antigen (PSMA)-targeting
small molecule–drug conjugate (SMDC) strategy to address this
issue. This led to CQ-16, which achieved its targeting
to prostate tumor cells through binding to PSMA. Also, CQ-16 retained the PARP inhibitory activity and exhibited highly selective
antiproliferative activities between PSMA-positive and PSMA-negative
prostate cells. Moreover, the hematological toxicity observed in Olaparib
was not showing in the group of CQ-16 even at a high
dose of 390 mg/kg. Moreover, oral administration of CQ-16 exerted significant tumor growth inhibition in the 22Rv1 xenograft
mouse model. These above findings not only highlight the potential
of CQ-16 to overcome the hematological toxicity associated
with PARP inhibitors but also provide a strategy to develop an SMDC
with enhanced safety profiles.