Identification of KLHL12 Ligands Using Fragment-Based Methods

Waterson, Alex G. [Vanderbilt University School of Medicine, Nashville, TN (United States); Vanderbilt College of Arts and Sciences, Nashville, TN (United States)] (ORCID:0000000201535723); Vadukoot, Anish [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Jana, Somnath [Vanderbilt Institute of Chemical Biology, Nashville, TN (United States)]; Cui, Jianwen [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Luong, Kelvin [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Rietz, Tyson A. [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000346705279); Madrigal-Carrillo, Ezequiel Alejandro [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Lehmann, Brian D. [Vanderbilt University Medical Center, Nashville, TN (United States)]; Sensintaffar, John L. [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Zhao, Bin [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Amporndanai, Kangsa [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000185279394); Petros, Zoe A. [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Scaggs, William Rush [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Chacon Simon, Selena [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Vekariya, Rakesh H. [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000182929793); Kim, Kwangho [Vanderbilt College of Arts and Sciences, Nashville, TN (United States); Vanderbilt Institute of Chemical Biology, Nashville, TN (United State)]; Thangaraj, Manikandan [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Christov, Plamen P. [Vanderbilt Institute of Chemical Biology, Nashville, TN (United States)]; South, Taylor M. [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Sai, Jiqing [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Thiruvaipati, Anusha [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Schmidt, Charles R. [Reaction Biology Corporation, Malvern, PA (United States)]; Eells, Rebecca [Reaction Biology Corporation, Malvern, PA (United States)]; Moore, William J. [NCI Center for Cancer Research, Frederick, MD (United States)]; Olejniczak, Edward T. [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Phan, Jason [Vanderbilt University School of Medicine, Nashville, TN (United States)]; Fesik, Stephen W. [Vanderbilt University School of Medicine, Nashville, TN (United States); Vanderbilt College of Arts and Sciences, Nashville, TN (United States)] (ORCID:0000000159576192)

doi:10.1021/acs.jmedchem.5c02931

DOE OSTI · 3029932

Identification of KLHL12 Ligands Using Fragment-Based Methods

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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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Waterson, Alex G. [Vanderbilt University School of Medicine, Nashville, TN (United States); Vanderbilt College of Arts and Sciences, Nashville, TN (United States)] (ORCID:0000000201535723), Vadukoot, Anish [Vanderbilt University School of Medicine, Nashville, TN (United States)], Jana, Somnath [Vanderbilt Institute of Chemical Biology, Nashville, TN (United States)], Cui, Jianwen [Vanderbilt University School of Medicine, Nashville, TN (United States)], Luong, Kelvin [Vanderbilt University School of Medicine, Nashville, TN (United States)], Rietz, Tyson A. [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000346705279), Madrigal-Carrillo, Ezequiel Alejandro [Vanderbilt University School of Medicine, Nashville, TN (United States)], Lehmann, Brian D. [Vanderbilt University Medical Center, Nashville, TN (United States)], Sensintaffar, John L. [Vanderbilt University School of Medicine, Nashville, TN (United States)], Zhao, Bin [Vanderbilt University School of Medicine, Nashville, TN (United States)], Amporndanai, Kangsa [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000185279394), Petros, Zoe A. [Vanderbilt University School of Medicine, Nashville, TN (United States)], Scaggs, William Rush [Vanderbilt University School of Medicine, Nashville, TN (United States)], Chacon Simon, Selena [Vanderbilt University School of Medicine, Nashville, TN (United States)], Vekariya, Rakesh H. [Vanderbilt University School of Medicine, Nashville, TN (United States)] (ORCID:0000000182929793), Kim, Kwangho [Vanderbilt College of Arts and Sciences, Nashville, TN (United States); Vanderbilt Institute of Chemical Biology, Nashville, TN (United State)], Thangaraj, Manikandan [Vanderbilt University School of Medicine, Nashville, TN (United States)], Christov, Plamen P. [Vanderbilt Institute of Chemical Biology, Nashville, TN (United States)], South, Taylor M. [Vanderbilt University School of Medicine, Nashville, TN (United States)], Sai, Jiqing [Vanderbilt University School of Medicine, Nashville, TN (United States)], Thiruvaipati, Anusha [Vanderbilt University School of Medicine, Nashville, TN (United States)], Schmidt, Charles R. [Reaction Biology Corporation, Malvern, PA (United States)], Eells, Rebecca [Reaction Biology Corporation, Malvern, PA (United States)], Moore, William J. [NCI Center for Cancer Research, Frederick, MD (United States)], Olejniczak, Edward T. [Vanderbilt University School of Medicine, Nashville, TN (United States)], Phan, Jason [Vanderbilt University School of Medicine, Nashville, TN (United States)], Fesik, Stephen W. [Vanderbilt University School of Medicine, Nashville, TN (United States); Vanderbilt College of Arts and Sciences, Nashville, TN (United States)] (ORCID:0000000159576192). 2026-03-29. Identification of KLHL12 Ligands Using Fragment-Based Methods. https://doi.org/10.1021/acs.jmedchem.5c02931

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