2. Academic Validation
  3. Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

  • Sci Rep. 2021 Apr 15;11(1):8313. doi: 10.1038/s41598-021-87817-4.
Philipp Rühl # 1,  Anna Scotto Rosato # 2,  Nicole Urban # 3,  Susanne Gerndt 1,  Rachel Tang 2,  Carla Abrahamian 2,  Charlotte Leser 1,  Jiansong Sheng 4,  Archana Jha 5,  Günter Vollmer 6,  Michael Schaefer 7,  Franz Bracher 8,  Christian Grimm 9
Affiliations

Affiliations

  • 1 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Munich, Germany.
  • 2 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.
  • 3 Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany.
  • 4 CiPA LAB, LLC, Gaitherburg, MD, USA.
  • 5 Casma Therapeutics Inc, Cambridge, MA, USA.
  • 6 Institute of Zoology, Molecular Cell Physiology and Endocrinology, University of Dresden, Dresden, Germany.
  • 7 Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany. [email protected].
  • 8 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University, Munich, Germany. [email protected].
  • 9 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 33859333 DOI: 10.1038/s41598-021-87817-4
Abstract

The cation channel TRPML1 is an important regulator of lysosomal function and Autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in Cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the Estrogen Receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: Autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast Cancer cell migration and invasion.

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