Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

David J. Leaver, Benjamin Cleary, Nghi Nguyen, Daniel Priebbenow, H. Rachel Lagiakos, Julie Sanchez, Lian Xue, Fei Huang, Yuxin Sun, Prashant Mujumdar, Ramesh Mudududdla, Swapna Varghese, Silvia Teguh, Susan A. Charman, Karen L. White, Kasiram Katneni, Matthew Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. Walters & 10 others Ian P. Street, Brendon J. Monahan, Kate E. Jarman, Helene Jousset Sabroux, Hendrik Falk, Matthew C. Chung, Stefan J. Hermans, Michael W. Parker, Tim Thomas, Jonathan B. Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.

Original languageEnglish
Pages (from-to)7146-7159
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number15
DOIs
Publication statusPublished - 8 Aug 2019

Cite this

Leaver, David J. ; Cleary, Benjamin ; Nguyen, Nghi ; Priebbenow, Daniel ; Lagiakos, H. Rachel ; Sanchez, Julie ; Xue, Lian ; Huang, Fei ; Sun, Yuxin ; Mujumdar, Prashant ; Mudududdla, Ramesh ; Varghese, Swapna ; Teguh, Silvia ; Charman, Susan A. ; White, Karen L. ; Katneni, Kasiram ; Cuellar, Matthew ; Strasser, Jessica M. ; Dahlin, Jayme L. ; Walters, Michael A. ; Street, Ian P. ; Monahan, Brendon J. ; Jarman, Kate E. ; Sabroux, Helene Jousset ; Falk, Hendrik ; Chung, Matthew C. ; Hermans, Stefan J. ; Parker, Michael W. ; Thomas, Tim ; Baell, Jonathan B. / Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 15. pp. 7146-7159.
@article{32782823eae949678c167069365de90d,
title = "Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A",
abstract = "A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.",
author = "Leaver, {David J.} and Benjamin Cleary and Nghi Nguyen and Daniel Priebbenow and Lagiakos, {H. Rachel} and Julie Sanchez and Lian Xue and Fei Huang and Yuxin Sun and Prashant Mujumdar and Ramesh Mudududdla and Swapna Varghese and Silvia Teguh and Charman, {Susan A.} and White, {Karen L.} and Kasiram Katneni and Matthew Cuellar and Strasser, {Jessica M.} and Dahlin, {Jayme L.} and Walters, {Michael A.} and Street, {Ian P.} and Monahan, {Brendon J.} and Jarman, {Kate E.} and Sabroux, {Helene Jousset} and Hendrik Falk and Chung, {Matthew C.} and Hermans, {Stefan J.} and Parker, {Michael W.} and Tim Thomas and Baell, {Jonathan B.}",
year = "2019",
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doi = "10.1021/acs.jmedchem.9b00665",
language = "English",
volume = "62",
pages = "7146--7159",
journal = "Journal of Medicinal Chemistry",
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Leaver, DJ, Cleary, B, Nguyen, N, Priebbenow, D, Lagiakos, HR, Sanchez, J, Xue, L, Huang, F, Sun, Y, Mujumdar, P, Mudududdla, R, Varghese, S, Teguh, S, Charman, SA, White, KL, Katneni, K, Cuellar, M, Strasser, JM, Dahlin, JL, Walters, MA, Street, IP, Monahan, BJ, Jarman, KE, Sabroux, HJ, Falk, H, Chung, MC, Hermans, SJ, Parker, MW, Thomas, T & Baell, JB 2019, 'Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A', Journal of Medicinal Chemistry, vol. 62, no. 15, pp. 7146-7159. https://doi.org/10.1021/acs.jmedchem.9b00665

Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A. / Leaver, David J.; Cleary, Benjamin; Nguyen, Nghi; Priebbenow, Daniel; Lagiakos, H. Rachel; Sanchez, Julie; Xue, Lian; Huang, Fei; Sun, Yuxin; Mujumdar, Prashant; Mudududdla, Ramesh; Varghese, Swapna; Teguh, Silvia; Charman, Susan A.; White, Karen L.; Katneni, Kasiram; Cuellar, Matthew; Strasser, Jessica M.; Dahlin, Jayme L.; Walters, Michael A.; Street, Ian P.; Monahan, Brendon J.; Jarman, Kate E.; Sabroux, Helene Jousset; Falk, Hendrik; Chung, Matthew C.; Hermans, Stefan J.; Parker, Michael W.; Thomas, Tim; Baell, Jonathan B.

In: Journal of Medicinal Chemistry, Vol. 62, No. 15, 08.08.2019, p. 7146-7159.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

AU - Leaver, David J.

AU - Cleary, Benjamin

AU - Nguyen, Nghi

AU - Priebbenow, Daniel

AU - Lagiakos, H. Rachel

AU - Sanchez, Julie

AU - Xue, Lian

AU - Huang, Fei

AU - Sun, Yuxin

AU - Mujumdar, Prashant

AU - Mudududdla, Ramesh

AU - Varghese, Swapna

AU - Teguh, Silvia

AU - Charman, Susan A.

AU - White, Karen L.

AU - Katneni, Kasiram

AU - Cuellar, Matthew

AU - Strasser, Jessica M.

AU - Dahlin, Jayme L.

AU - Walters, Michael A.

AU - Street, Ian P.

AU - Monahan, Brendon J.

AU - Jarman, Kate E.

AU - Sabroux, Helene Jousset

AU - Falk, Hendrik

AU - Chung, Matthew C.

AU - Hermans, Stefan J.

AU - Parker, Michael W.

AU - Thomas, Tim

AU - Baell, Jonathan B.

PY - 2019/8/8

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SN - 0022-2623

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