Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

David J. Leaver; Benjamin Cleary; Nghi Nguyen; Daniel L. 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; 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

doi:10.1021/acs.jmedchem.9b00665

Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

David J. Leaver, Benjamin Cleary, Nghi Nguyen, Daniel L. 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. WaltersIan 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

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31 Citations (Scopus)

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 language	English
Pages (from-to)	7146-7159
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00665
Publication status	Published - 08 Aug 2019

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Leaver, D. J., Cleary, B., Nguyen, N., Priebbenow, D. L., Lagiakos, H. R., Sanchez, J., Xue, L., Huang, F., Sun, Y., Mujumdar, P., Mudududdla, R., Varghese, S., Teguh, S., Charman, S. A., White, K. L., Katneni, K., Cuellar, M., Strasser, J. M., Dahlin, J. L., ... Baell, J. B. (2019). Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A. Journal of Medicinal Chemistry, 62(15), 7146-7159. https://doi.org/10.1021/acs.jmedchem.9b00665

@article{c6d93d1e1d0049058b81a80bd44f5527,

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 Priebbenow, \{Daniel L.\} 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.\}",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = aug,

day = "8",

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, DL, 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

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 L.

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

Y1 - 2019/8/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85071190923

UR - https://www.scopus.com/inward/citedby.url?scp=85071190923&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.9b00665

DO - 10.1021/acs.jmedchem.9b00665

M3 - Article

C2 - 31256587

AN - SCOPUS:85071190923

SN - 0022-2623

VL - 62

SP - 7146

EP - 7159

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

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