2. Academic Validation
  3. Identification of highly potent and selective HTRA1 inhibitors

Identification of highly potent and selective HTRA1 inhibitors

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129814. doi: 10.1016/j.bmcl.2024.129814.
David G Dennis 1,  Young Joo Sun 2,  Dylan E Parsons 1,  Vinit B Mahajan 3,  Mark Smith 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA; Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA.
  • 2 Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA.
  • 3 Molecular Surgery Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, CA 94304, USA; Veterans Affairs Palo Alto Health Care System, CA 94304, USA. Electronic address: vinit.mahajan@stanford.com.
  • 4 Medicinal Chemistry Knowledge Center, Sarafan ChEM-H, Stanford University, CA 94305, USA. Electronic address: mxsmith@stanford.edu.
PMID: 38815872 DOI: 10.1016/j.bmcl.2024.129814
Abstract

High temperature requirement A serine peptidase 1 (HTRA1) is a serine Protease involved in an array of signaling pathways. It is also responsible for the regulation of protein aggregates via refolding, translocation, and degradation. It has subsequently been found that runaway proteolytic HTRA1 activity plays a role in a variety of diseases, including Age-Related Macular Degeneration (AMD), osteoarthritis, and Rheumatoid Arthritis. Selective inhibition of serine Protease HTRA1 therefore offers a promising new strategy for the treatment of these diseases. Herein we disclose structure-activity-relationship (SAR) studies which identify key interactions responsible for binding affinity of small molecule inhibitors to HTRA1. The study results in highly potent molecules with IC50's less than 15 nM and excellent selectivity following a screen of 35 proteases.

Keywords

Age-related macular degeneration; HTRA1; Peptidomimetics; Protease inhibitor; Structure–activity relationship studies.

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