Identification of KLHL12 Ligands Using Fragment-Based Methods

  • J Med Chem. 2026 Apr 9;69(7):7709-7731. doi: 10.1021/acs.jmedchem.5c02931.
Alex G Waterson  1  2 ,  Anish Vadukoot  3 ,  Somnath Jana  4 ,  Jianwen Cui  3 ,  Kelvin Luong  3 ,  Tyson A Rietz  3 ,  Ezequiel Alejandro Madrigal-Carrillo  3 ,  Brian D Lehmann  5 ,  John L Sensintaffar  3 ,  Bin Zhao  3 ,  Kangsa Amporndanai  3 ,  Zoe A Petros  3 ,  William Rush Scaggs  3 ,  Selena Chacon Simon  3 ,  Rakesh H Vekariya  3 ,  Kwangho Kim  2  4 ,  Manikandan Thangaraj  3 ,  Plamen P Christov  4 ,  Taylor M South  3 ,  Jiqing Sai  3 ,  Anusha Thiruvaipati  3 ,  Charles R Schmidt  6 ,  Rebecca Eells  6 ,  William J Moore  7 ,  Edward T Olejniczak  3 ,  Jason Phan  3 ,  Stephen W Fesik  1  2  3
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 2. Department of Chemistry, Vanderbilt College of Arts and Sciences, Nashville, Tennessee 37232, United States.
  • 3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4. Molecular Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37232, United States.
  • 5. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 6. Reaction Biology Corporation, Malvern, Pennsylvania 19355, United States.
  • 7. NCI Center for Cancer Research, Frederick, Maryland 21701, United States.
PMID: 41906311 DOI: 10.1021/acs.jmedchem.5c02931
Abstract

Targeted protein degradation can be induced by recruiting a protein of interest to an E3 Ligase, resulting in its ubiquitination and subsequent proteasome-mediated degradation. However, only a small number of E3 Ligases have been utilized for degradation. Expansion of the repertoire of useful E3 Ligases via the identification of ligands to those ligases could broaden the scope and applicability of the degradation paradigm. We have identified KLHL12 as an E3 Ligase with higher expression in Cancer over normal tissues. We report here the use of NMR-based screening to identify fragments that bind to KLHL12, and X-ray structures of a fragment hit bound to KLHL12. Using this structural information, we optimized the hits, leading to the first reported small molecules that bind to KLHL12 with submicromolar affinity. Derivatives of these compounds may be useful for the construction of PROTACs to selectively degrade protein targets in tumors while sparing normal cells.

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