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

  • J Med Chem. 2024 Nov 14;67(21):19586-19611. doi: 10.1021/acs.jmedchem.4c01910.
Qi Chen  1 ,  Zhenying Wu  1 ,  Haiying Zhu  1  2 ,  Xi Zhang  1  3 ,  Yongping Yu  1  3  4 ,  Wenteng Chen  1  3
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 2. School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 3. Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China.
  • 4. School of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830054, China.
PMID: 39482858 DOI: 10.1021/acs.jmedchem.4c01910
Abstract

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.

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