@article{e216bf7ff2f44bb4a71526b33331cd11,
title = "Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer",
abstract = "KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.",
keywords = "breast cancer, cell cycle, CTx-648, epigenetics, estrogen receptor, KAT6A, KAT6B, PF-9363, resistance",
author = "Shikhar Sharma and Chung, {Chi Yeh} and Sean Uryu and Jelena Petrovic and Joan Cao and Amanda Rickard and Nataliya Nady and Samantha Greasley and Eric Johnson and Oleg Brodsky and Showkhin Khan and Hui Wang and Zhenxiong Wang and Yong Zhang and Konstantinos Tsaparikos and Lei Chen and Anthony Mazurek and John Lapek and Kung, {Pei Pei} and Scott Sutton and Richardson, {Paul F.} and Greenwald, {Eric C.} and Shinji Yamazaki and Rhys Jones and Maegley, {Karen A.} and Patrick Bingham and Hieu Lam and Stupple, {Alexandra E.} and Aileen Kamal and Anderly Chueh and Anthony Cuzzupe and Morrow, {Benjamin J.} and Bin Ren and Catalina Carrasco-Pozo and Tan, {Chin Wee} and Bhuva, {Dharmesh D.} and Elizabeth Allan and Elliot Surgenor and Fran{\c c}ois Vaillant and Havva Pehlivanoglu and Hendrik Falk and Whittle, {James R.} and Janet Newman and Joseph Cursons and Doherty, {Judy P.} and White, {Karen L.} and Laura MacPherson and Mark Devlin and Dennis, {Matthew L.} and Hattarki, {Meghan K.} and {De Silva}, Melanie and Camerino, {Michelle A.} and Butler, {Miriam S.} and Olan Dolezal and Patricia Pilling and Richard Foitzik and Stupple, {Paul A.} and Lagiakos, {H. Rachel} and Walker, {Scott R.} and Soroor Hediyeh-Zadeh and Stewart Nuttall and Spall, {Sukhdeep K.} and Charman, {Susan A.} and Theresa Connor and Peat, {Thomas S.} and Avery, {Vicky M.} and Bozikis, {Ylva E.} and Yuqing Yang and Ming Zhang and Monahan, {Brendon J.} and Voss, {Anne K.} and Tim Thomas and Street, {Ian P.} and Dawson, {Sarah Jane} and Dawson, {Mark A.} and Lindeman, {Geoffrey J.} and Davis, {Melissa J.} and Visvader, {Jane E.} and Paul, {Thomas A.}",
note = "Funding Information: S.S., T.A.P., C.Y.C., S.U., J.P., J.C., A.R., N.N., S.G., E.J., O.B., S.K., H.W., Z.W., Y.Z., K.T., L.C., A.M., J.L., P.P.K., S.S., P.F.R., E.C.G., S.Y., R.J., K.A.M., P.B., and H.L. are/were employees of Pfizer and some of the authors are shareholders in Pfizer Inc. L.C. and A.M. are co-inventors on patent WO2022013369. P.S., H.R.L., B.J.M., R.F., C.H., M.C., Y.B., and S.W. are inventors on patent WO2019243491 and have received payments from Monash University derived from distribution of licensing income received from Pfizer. P.P.K., S.S., P.F.R., Y.B., and P.S. are inventors on patent WO2020254946. P.S. is an inventor on patent WO2022013369. T.T., H.R.L and A.K.V. are inventors on patent WO2016198507 A1. The Thomas and Voss laboratories received research funding from the Cooperative Research Centre (CRC) for Cancer Therapeutics (CTx), Australia. T.T. and A.K.V. have received payments from a distribution of the licensing income from Pfizer for serving on an advisory board meeting for Pfizer. M.A.D. has been a member of advisory boards for CTX CRC, GSK, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of advisory boards for Adela. M.A.D. and S.-J.D. receive research funding from CTx CRC and from the Pfizer Emerging Science Fund. Ian Street is a member of the Scientific Advisory Board of Oncology One Pty Ltd and has received payments from distribution of licensing income from Pfizer. J.N. is currently an adjunct professor at the University of New South Wales, Kensington, NSW, Australia. M.J.D and D.D.B. are currently working at South Australian immunoGENomics Cancer Institute (SAiGENCI), Faculty of Health and Medical Sciences, The University of Adelaide. J.C. is a current employee of oNKo-innate Pty Ltd. J.L. is currently an employee and shareholder of Belharra Therapeutics. Funding Information: The authors would like to thank Mats Ljungman (University of Michigan) for help with Bru-seq experiments, UCSD Center for Epigenome for ATAC-seq sample preparation & analysis, Northwestern Proteomics Core for epiproteomic histone modification analysis, Zhengang Peng (WuXi) and HDB for assisting with CRISPR experiments and breast cancer BOE. We are grateful to Athena Huei Chen, Nichol Miller, and Aidong Wu for help with cellular & biochemical assay development, Goknur Giner for bioinformatic advice, and Catherine Lee & Colin Flaveny for acquisition of in vivo data during development of CTx-648. We would also like to thank Anand Gautam and Stephanie Shi for help managing the Pfizer & Cancer Therapeutics CRC research collaboration and to Tao Xie, Lei Bao, Wenyan Zhong, Maximillian Follettie, and Philip Tedeschi for their efforts in the early phase of this project. The Cancer Therapeutics Cooperative Research Centre (CTx) was funded by the Australian Federal Government{\textquoteright}s Cooperative Research Centre scheme. All sources of funding for the research reported here were supported by Pfizer . Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = oct,
day = "19",
doi = "10.1016/j.chembiol.2023.07.005",
language = "English",
volume = "30",
pages = "1191--1210",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Cell Press",
number = "10",
}
