Drugging the undruggable — KATing away at cancer

David Leaver

Abstract

Are the histone lysine acetyltransferase families (KATs) druggable? This question has been frequently asked in the field of epigenetics and for many decades KATs were considered undruggable biochemical targets. KAT6A is an oncogene and it is anticipated that selective inhibitors of KAT6A will help with the development of novel anticancer drugs. A high-throughput screen for KAT6A inhibitors led to the discovery of the benzoylnaphthalene-2-sulfonohydrazide CTX-0124143 as a moderate inhibitor of KAT6A (IC50 = 1.0 μM). Exploration of the structure-activity relationships (SAR) and sequential medicinal chemistry optimization facilitated the discovery of WM-8014 as a potent inhibitor of KAT6A (IC50 = 0.008 μM) [1,2]. WM-8014 was shown to potentiate oncogene-induced senescence in vitro and in a zebrafish model, while WM-1119 was shown to arrest lymphoma progression in mice [1,3].

References
[1] Baell, J. B.; Leaver, D. J.; Hermans, S. J. et al. Inhibitors of Histone Acetyltransferases KAT6A/B Induce Senescence and Arrest Tumour Growth. Nature 2018, 560, 253−257.
[2] Leaver, D. J.; Cleary, B.; Nguyen, N. et al. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A. J. Med. Chem. 2019, 62, 7146−7159.
[3] Priebbenow, D. L.; Leaver, D. J.; Nguyen, N. et al. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents. J. Med. Chem. 2020, 63, 4655-4684.

Original language	English
Pages	52
Number of pages	1
Publication status	Published - 2025
Event	Medicinal Chemistry & Chemical Biology Conference 2025 : MCCB 2025 - DoubleTree by Hilton Hotel on the Esplanade, Darwin, Australia Duration: 13 Apr 2025 → 16 Apr 2025 https://web.archive.org/web/20250312025409/https://mccb2025.com.au/ (Conference website on Wayback Machine) https://www.raci.org.au/events-and-awards/events/mccbdocuments (Program and abstract book)

Conference

Conference	Medicinal Chemistry & Chemical Biology Conference 2025
Abbreviated title	Drug Discovery in the Territory
Country/Territory	Australia
City	Darwin
Period	13/04/25 → 16/04/25
Other	The MCCB 2025 Conference is the national meeting of the RACI Medicinal Chemistry and Chemical Biology Division. The MCCB 2025 meeting, which will be both inclusive and diverse, will bring together academic and industry experts from Australia and internationally to discuss the latest innovations and developments in Medicinal Chemistry and Chemical Biology research. The program will showcase the very best research and innovations from the Australian academic and industry sectors on drug discovery and chemical probes, including methods for hit and target identification, development of new biologically active entities, probing complex biology, and new approaches to tackling diseases. We look forward to welcoming you to Darwin, the capital of the tropical north and the gateway to Kakadu National Park and the Australian outback.
Internet address	https://web.archive.org/web/20250312025409/https://mccb2025.com.au/ (Conference website on Wayback Machine) https://www.raci.org.au/events-and-awards/events/mccbdocuments (Program and abstract book)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

3 Article

Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents
Priebbenow, D. L., Leaver, D. J., Nguyen, N., Cleary, B., 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., Shackleford, D. M., Katneni, K., Cuellar, M., Strasser, J. M. & Dahlin, J. L. & 13 others, Walters, M. A., Street, I. P., Monahan, B. J., Jarman, K. E., Jousset Sabroux, H., Falk, H., Chung, M. C., Hermans, S. J., Downer, N. L., Parker, M. W., Voss, A. K., Thomas, T. & Baell, J. B., 14 May 2020, In: Journal of Medicinal Chemistry. 63, 9, p. 4655-4684 30 p.
Research output: Contribution to journal › Article › peer-review
26 Link opens in a new tab Citations (Scopus)
Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A
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. & Walters, M. A. & 10 others, Street, I. P., Monahan, B. J., Jarman, K. E., Sabroux, H. J., Falk, H., Chung, M. C., Hermans, S. J., Parker, M. W., Thomas, T. & Baell, J. B., 08 Aug 2019, In: Journal of Medicinal Chemistry. 62, 15, p. 7146-7159 14 p.
Research output: Contribution to journal › Article › peer-review
37 Link opens in a new tab Citations (Scopus)
Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth
Baell, J. B., Leaver, D., Hermans, S. J., Kelly, G. L., Brennan, M. S., Downer, N. L., Nguyen, N., Wichmann, J., McRae, H. M., Yang, Y., Cleary, B., Lagiakos, H. R., Mieruszynski, S., Pacini, G., Vanyai, H. K., Bergamasco, M. I., May, R. E., Davey, B. K., Morgan, K. J. & Sealey, A. J. & 32 others, Wang, B., Zamudio, N., Wilcox, S., Garnham, A. L., Sheikh, B. N., Aubrey, B. J., Doggett, K., Chung, M. C., de Silva, M., Bentley, J., Pilling, P., Hattarki, M., Dolezal, O., Dennis, M. L., Falk, H., Ren, B., Charman, S. A., White, K. L., Rautela, J., Newbold, A., Hawkins, E. D., Johnstone, R. W., Huntington, N. D., Peat, T. S., Heath, J. K., Strasser, A., Parker, M. W., Smyth, G. K., Street, I. P., Monahan, B. J., Voss, A. K. & Thomas, T., 19 Aug 2018, In: Nature. 560, p. 253-257 21 p.
Research output: Contribution to journal › Article › peer-review
263 Link opens in a new tab Citations (Scopus)

Cite this

@conference{ea8196c451d7456fac9a782f3c01294a,

title = "Drugging the undruggable — KATing away at cancer",

abstract = "Are the histone lysine acetyltransferase families (KATs) druggable? This question has been frequently asked in the field of epigenetics and for many decades KATs were considered undruggable biochemical targets. KAT6A is an oncogene and it is anticipated that selective inhibitors of KAT6A will help with the development of novel anticancer drugs. A high-throughput screen for KAT6A inhibitors led to the discovery of the benzoylnaphthalene-2-sulfonohydrazide CTX-0124143 as a moderate inhibitor of KAT6A (IC50 = 1.0 μM). Exploration of the structure-activity relationships (SAR) and sequential medicinal chemistry optimization facilitated the discovery of WM-8014 as a potent inhibitor of KAT6A (IC50 = 0.008 μM) [1,2]. WM-8014 was shown to potentiate oncogene-induced senescence in vitro and in a zebrafish model, while WM-1119 was shown to arrest lymphoma progression in mice [1,3]. References [1] Baell, J. B.; Leaver, D. J.; Hermans, S. J. et al. Inhibitors of Histone Acetyltransferases KAT6A/B Induce Senescence and Arrest Tumour Growth. Nature 2018, 560, 253−257. [2] Leaver, D. J.; Cleary, B.; Nguyen, N. et al. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A. J. Med. Chem. 2019, 62, 7146−7159. [3] Priebbenow, D. L.; Leaver, D. J.; Nguyen, N. et al. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents. J. Med. Chem. 2020, 63, 4655-4684.",

author = "David Leaver",

year = "2025",

language = "English",

pages = "52",

note = "Medicinal Chemistry \& Chemical Biology Conference 2025 : MCCB 2025, Drug Discovery in the Territory ; Conference date: 13-04-2025 Through 16-04-2025",

url = "https://web.archive.org/web/20250312025409/https://mccb2025.com.au/, https://www.raci.org.au/events-and-awards/events/mccbdocuments",

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TY - CONF

T1 - Drugging the undruggable — KATing away at cancer

AU - Leaver, David

PY - 2025

Y1 - 2025

N2 - Are the histone lysine acetyltransferase families (KATs) druggable? This question has been frequently asked in the field of epigenetics and for many decades KATs were considered undruggable biochemical targets. KAT6A is an oncogene and it is anticipated that selective inhibitors of KAT6A will help with the development of novel anticancer drugs. A high-throughput screen for KAT6A inhibitors led to the discovery of the benzoylnaphthalene-2-sulfonohydrazide CTX-0124143 as a moderate inhibitor of KAT6A (IC50 = 1.0 μM). Exploration of the structure-activity relationships (SAR) and sequential medicinal chemistry optimization facilitated the discovery of WM-8014 as a potent inhibitor of KAT6A (IC50 = 0.008 μM) [1,2]. WM-8014 was shown to potentiate oncogene-induced senescence in vitro and in a zebrafish model, while WM-1119 was shown to arrest lymphoma progression in mice [1,3]. References [1] Baell, J. B.; Leaver, D. J.; Hermans, S. J. et al. Inhibitors of Histone Acetyltransferases KAT6A/B Induce Senescence and Arrest Tumour Growth. Nature 2018, 560, 253−257. [2] Leaver, D. J.; Cleary, B.; Nguyen, N. et al. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A. J. Med. Chem. 2019, 62, 7146−7159. [3] Priebbenow, D. L.; Leaver, D. J.; Nguyen, N. et al. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents. J. Med. Chem. 2020, 63, 4655-4684.

AB - Are the histone lysine acetyltransferase families (KATs) druggable? This question has been frequently asked in the field of epigenetics and for many decades KATs were considered undruggable biochemical targets. KAT6A is an oncogene and it is anticipated that selective inhibitors of KAT6A will help with the development of novel anticancer drugs. A high-throughput screen for KAT6A inhibitors led to the discovery of the benzoylnaphthalene-2-sulfonohydrazide CTX-0124143 as a moderate inhibitor of KAT6A (IC50 = 1.0 μM). Exploration of the structure-activity relationships (SAR) and sequential medicinal chemistry optimization facilitated the discovery of WM-8014 as a potent inhibitor of KAT6A (IC50 = 0.008 μM) [1,2]. WM-8014 was shown to potentiate oncogene-induced senescence in vitro and in a zebrafish model, while WM-1119 was shown to arrest lymphoma progression in mice [1,3]. References [1] Baell, J. B.; Leaver, D. J.; Hermans, S. J. et al. Inhibitors of Histone Acetyltransferases KAT6A/B Induce Senescence and Arrest Tumour Growth. Nature 2018, 560, 253−257. [2] Leaver, D. J.; Cleary, B.; Nguyen, N. et al. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A. J. Med. Chem. 2019, 62, 7146−7159. [3] Priebbenow, D. L.; Leaver, D. J.; Nguyen, N. et al. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents. J. Med. Chem. 2020, 63, 4655-4684.

M3 - Abstract

SP - 52

T2 - Medicinal Chemistry & Chemical Biology Conference 2025

Y2 - 13 April 2025 through 16 April 2025

ER -

Drugging the undruggable — KATing away at cancer

Abstract

Conference

UN SDGs

Fingerprint

Research output

Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents

Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

Cite this