2. Academic Validation
  3. Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1

Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1

  • Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2425494122. doi: 10.1073/pnas.2425494122.
Seow Theng Ong 1,  Young-Woo Nam 2,  Joshua A Nasburg 3,  Alena Ramanishka 2,  Xuan Rui Ng 1,  Zhong Zhuang 1,  Stephanie Shee Min Goay 1,  Hai M Nguyen 3,  Latika Singh 3,  Vikrant Singh 3,  Alicia Rivera 4 5,  M Elaine Eyster 6,  Yang Xu 7,  Seth L Alper 4 5,  Heike Wulff 3,  Miao Zhang 2,  K George Chandy 1
Affiliations

Affiliations

  • 1 Lee Kong Chian School of Medicine-Innovative CRO Explorer Collaborative Platform, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.
  • 2 Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618.
  • 3 Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616.
  • 4 Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215.
  • 5 Department of Medicine, Harvard Medical School, Boston, MA 02115.
  • 6 Division of Blood and Vascular Disorders, Department of Medicine, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033.
  • 7 Division of Cryogenic Electron Microscopy and Bioimaging, Stanford Synchrotron Radiation Lightsource, Stanford Linear Accelerator Center National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025.
PMID: 40294255 DOI: 10.1073/pnas.2425494122
Abstract

The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K+ channel KCA3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked KCA3.1 with an IC50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the KCA3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant KCA3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. KCA3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which KCA3.1 has been experimentally confirmed as a therapeutic target.

Keywords

1,4-dihydropyridine; KCa3.1/KCNN4; acute ischemic stroke; cryo-EM; hereditary xerocytosis.

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