On the search for TMBIM4 pharmacological inhibitors

The dysregulation of Ca2+ homeostasis is crucial in cancer initiation and progression. Cancer cells can establish cancer hallmarks features by manipulating the expression or activity of Ca2+ modulators, including pumps, channels, and exchangers. As an innovative approach, we propose to reprogram Ca2+ intracellular fluxes by inhibiting specific endoplasmic reticulum (ER) or Golgi apparatus (GA) Ca2+ channels to control glioma progression [1]. In particular, manipulating the expression of the GA Ca2+ channel TMBIM4 (transmembrane BAX inhibitor motif containing 4) impacts glioma cell invasion and in vivo tumour growth. Therefore, we aim at finding still unknown pharmacological inhibitors for TMBIM4. In our recently finished HPC FCT project (CPCA/A1/410638/2021: Fine-tuning TMBIM ion channel activity to control hallmarks of cancer), we used the crystal structures of the TMBIM homolog YetJ from Bacillus Subtilis (PDB: 6nq7, 6nq8) as a model for the TMBIM4 channel in the open and closed states [2]. In this communication, we will present molecular dynamics studies extending to the microsecond to clarify the best approach and methodology to be used, by disclosing the behavior of the channel after deprotonation of key residues.