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

Institute for Therapeutics Discovery and Development

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21 Scopus citations

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 (US)
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
State	Published - Aug 8 2019

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© 2019 American Chemical Society.

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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

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

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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.",

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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.

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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.

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Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

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