Optimization of selective antagonists for the TRPML2 lysosomal ion channel

The ion channel subfamily TRPML (Transient Receptor Potential channel Mucolipin) plays an important role in lysosomal and endosomal regulation, and TRPML2 participates directly in chemokine secretion and activation of inflammatory pathways, such as NF-κB. Remarkably, elevated levels of chemokines and increased expression of TRPML2 have been shown to be related with prostate adenocarcinoma (PCa) prognosis. A high throughput virtual screening nearly 2.3 million compounds against TRPML2 revealed the hit z193107974, with micromolar inhibitory activity. This work proposes hit validation by resynthesis, confirmatory biological assays and evaluation of anticancer properties. The calcium imaging assay confirmed the hit inhibitory activity with a potency of 32 μM for TRPML2, 33 μM for TRPML1 and an unexpected agonist activity against TRPML3 (24 μM). Extensive Molecular Dynamics Simulations (MD) highlighted the key features for TRPML binding. Soon, we expect to develop derivatives of the hit to construct an S.A.R. (Structure Activity Relationship).