2. Academic Validation
  3. Design and synthesis of dual cathepsin L and S inhibitors and antimetastatic activity evaluation in pancreatic cancer cells

Design and synthesis of dual cathepsin L and S inhibitors and antimetastatic activity evaluation in pancreatic cancer cells

  • Bioorg Med Chem Lett. 2023 Jan 15;80:129087. doi: 10.1016/j.bmcl.2022.129087.
Haoqiang Huang 1,  Yi Zhang 1,  Xiaohong Xu 2,  Yongzheng Liu 3,  Juanping Zhao 4,  Lili Ma 1,  Jie Lei 1,  Wentao Ge 1,  Ning Li 3,  Enlong Ma 4,  Yanchun Li 5,  Lei Yuan 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, PR China.
  • 2 Center for Drug Evaluation, NMPA, Beijing 100022, PR China.
  • 3 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 4 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
  • 6 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 36427655 DOI: 10.1016/j.bmcl.2022.129087
Abstract

Currently, the migration and invasion of Cancer cells remain the main factors of poor prognosis in the majority of Cancer patients. Developing an effective antimetastatic agent is crucial for Cancer therapy. Our recent research revealed that Cat L and S are expressed concurrently in metastatic pancreatic Cancer cells. Asperphenamate analog ASPER-29, which exhibits dual Cat L and S inhibitory potency, showed a definite antimetastatic effect on pancreatic Cancer BxPC-3 and PANC-1 cells. To further improve the antimetastatic ability of asperphenamate-type molecules, 24 derivatives were designed and synthesized by a scaffold-hopping strategy. The Cathepsin inhibitory activity assay results showed that most of the derivatives exhibited dual inhibitory effects on Cat L and S. Among all derivatives, Compound B1a showed the strongest inhibitory activity, with IC50 values of 4.10 ± 0.14 μM and 1.79 ± 0.11 μM, which were 1.5-fold and 2.8-fold more potent than those of positive drugs against Cat L and S, respectively. Further wound-healing and transwell chamber assays demonstrated that B1a presented significant antimetastatic ability in vitro.

Keywords

Antimetastatic ability; Asperphenamate; Cathepsin; Design and synthesis; Dual inhibitors.

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