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

Daniel L. Priebbenow; David J. Leaver; Nghi Nguyen; Benjamin Cleary; 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; David M. Shackleford; 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; Natalie L. Downer; Michael W. Parker; Anne K. Voss; Tim Thomas; Jonathan B. Baell

doi:10.1021/acs.jmedchem.9b02071

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

Daniel L. Priebbenow, David J. Leaver, Nghi Nguyen, Benjamin Cleary, 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, David M. Shackleford, Kasiram Katneni, Matthew Cuellar, Jessica M. Strasser, Jayme L. DahlinMichael A. Walters, Ian P. Street, Brendon J. Monahan, Kate E. Jarman, Helene Jousset Sabroux, Hendrik Falk, Matthew C. Chung, Stefan J. Hermans, Natalie L. Downer, Michael W. Parker, Anne K. Voss, Tim Thomas, Jonathan B. Baell

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9 Scopus citations

Abstract

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC₅₀ of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC₅₀ = 6.3 nM; K_D = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

Original language	English (US)
Pages (from-to)	4655-4684
Number of pages	30
Journal	Journal of medicinal chemistry
Volume	63
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.9b02071
State	Published - May 14 2020

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© 2020 American Chemical Society

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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., ... Baell, J. B. (2020). Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents. Journal of medicinal chemistry, 63(9), 4655-4684. https://doi.org/10.1021/acs.jmedchem.9b02071

Priebbenow, DL, Leaver, DJ, Nguyen, N, Cleary, B, Lagiakos, HR, Sanchez, J, Xue, L, Huang, F, Sun, Y, Mujumdar, P, Mudududdla, R, Varghese, S, Teguh, S, Charman, SA, White, KL, Shackleford, DM, Katneni, K, Cuellar, M, Strasser, JM, Dahlin, JL, Walters, MA, Street, IP, Monahan, BJ, Jarman, KE, Jousset Sabroux, H, Falk, H, Chung, MC, Hermans, SJ, Downer, NL, Parker, MW, Voss, AK, Thomas, T & Baell, JB 2020, 'Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents', Journal of medicinal chemistry, vol. 63, no. 9, pp. 4655-4684. https://doi.org/10.1021/acs.jmedchem.9b02071

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

abstract = "A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.",

author = "Priebbenow, {Daniel L.} and Leaver, {David J.} and Nghi Nguyen and Benjamin Cleary 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 Shackleford, {David M.} 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 {Jousset Sabroux}, Helene and Hendrik Falk and Chung, {Matthew C.} and Hermans, {Stefan J.} and Downer, {Natalie L.} and Parker, {Michael W.} and Voss, {Anne K.} and Tim Thomas and Baell, {Jonathan B.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Chemical Society",

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doi = "10.1021/acs.jmedchem.9b02071",

language = "English (US)",

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T1 - Discovery of acylsulfonohydrazide-derived inhibitors of the lysine acetyltransferase, kat6a, as potent senescence-inducing anti-cancer agents

AU - Priebbenow, Daniel L.

AU - Leaver, David J.

AU - Nguyen, Nghi

AU - Cleary, Benjamin

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 - Shackleford, David M.

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 - Jousset Sabroux, Helene

AU - Falk, Hendrik

AU - Chung, Matthew C.

AU - Hermans, Stefan J.

AU - Downer, Natalie L.

AU - Parker, Michael W.

AU - Voss, Anne K.

AU - Thomas, Tim

AU - Baell, Jonathan B.

PY - 2020/5/14

Y1 - 2020/5/14

N2 - A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

AB - A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

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

Abstract

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