Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer

Area of Science:

• Oncology
• Medicinal Chemistry
• Cancer Biology

Background:

• Oesophageal cancer (OC) is a leading cause of cancer mortality globally, characterized by high heterogeneity and limited therapeutic success with current targeted and immunotherapy agents.
• Kinase dysregulation is implicated in OC oncogenesis and progression, yet kinase-targeted therapies have yielded suboptimal outcomes.
• The pyrazolo[3,4-d]pyrimidine scaffold possesses known pharmacological properties relevant for drug development.

Purpose of the Study:

• To develop novel antiproliferative inhibitors for oesophageal cancer using a ligand-centered strategy combined with phenotypic screening.
• To accelerate the discovery of lead compounds for highly heterogeneous cancers like OC.
• To identify specific kinase targets for novel OC therapeutics.

Main Methods:

• Synthesis and testing of 54 novel pyrazolo[3,4-d]pyrimidine derivatives against OC cell lines.
• Utilized a ligand-centered drug design approach coupled with phenotypic screening.
• Employed an iterative structure-antiproliferative activity relationship (SAAR) process.

Main Results:

• The lead compound, 2D7 (eCCA352), demonstrated pan-oesophageal cancer activity and induced cell cycle arrest at submicromolar concentrations.
• Compound 2D7 was identified as an inhibitor of Aurora kinase A.
• The study successfully generated a series of novel pyrazolo[3,4-d]pyrimidine derivatives with antiproliferative effects on OC cells.

Conclusions:

• The novel pyrazolo[3,4-d]pyrimidine derivative 2D7 is a promising lead compound for developing targeted anticancer agents against oesophageal cancer.
• Inhibition of Aurora kinase A by 2D7 presents a new therapeutic strategy for OC.
• The implemented ligand-centered and phenotypic screening approach is effective for discovering lead compounds in heterogeneous cancers.