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

Oesophageal cancer (OC) is one of the leading causes of cancer-related deaths worldwide. Due in part to its high heterogeneity, OC prognosis remains poor despite the introduction of targeted and immunotherapy drugs. Although numerous kinases play a significant role in the oncogenesis and progression of OC, targeting kinases have shown so far limited therapeutic success. Based on our understanding of the pharmacological properties of the pyrazolo[3,4-d]pyrimidine scaffold and the complex biology of OC, we implemented a ligand-centred strategy combined with phenotypic screening to develop novel antiproliferative inhibitors against OC. This approach is specifically designed to accelerate the discovery of lead compounds in cancers of high molecular heterogeneity such as OC. In an iterative process driven by structure-antiproliferative activity relationships (SAARs), we synthesised and tested 54 novel pyrazolo[3,4-d]pyrimidine derivatives against OC cell lines. The lead compound 2D7 (a.k.a. eCCA352) induces pan-OC activity and cell cycle arrest in the submicromolar range and was determined to inhibit Aurora kinase A, providing a new starting point to develop anticancer targeted agents against OC.