학술논문
Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.
Document Type
Academic Journal
Author
Sharma S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA. Electronic address: shikhar.sharma@pfizer.com.; Chung CY; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Uryu S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Petrovic J; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Cao J; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Rickard A; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Nady N; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Greasley S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Johnson E; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Brodsky O; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Khan S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Wang H; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Wang Z; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Zhang Y; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Tsaparikos K; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Chen L; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Mazurek A; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Lapek J; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Kung PP; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Sutton S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Richardson PF; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Greenwald EC; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Yamazaki S; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Jones R; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Maegley KA; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Bingham P; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Lam H; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.; Stupple AE; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; CANThera Discovery, Melbourne, VIC 3000, Australia.; Kamal A; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Chueh A; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Cuzzupe A; SYNthesis Med Chem (Australia) Pty Ltd, Bio21 Institute, 30 Flemington Road, Parkville, VIC 3052, Australia.; Morrow BJ; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia.; Ren B; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Carrasco-Pozo C; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Brisbane QLD 4111, Australia.; Tan CW; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Bhuva DD; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Allan E; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Surgenor E; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Vaillant F; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Pehlivanoglu H; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Falk H; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Whittle JR; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Newman J; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Cursons J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Doherty JP; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; White KL; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.; MacPherson L; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Devlin M; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Dennis ML; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Hattarki MK; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; De Silva M; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Camerino MA; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.; Butler MS; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Dolezal O; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Pilling P; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Foitzik R; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; OncologyOne Pty Ltd, Melbourne, VIC 3000, Australia.; Stupple PA; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; CANThera Discovery, Melbourne, VIC 3000, Australia.; Lagiakos HR; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.; Walker SR; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Hediyeh-Zadeh S; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Nuttall S; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Spall SK; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Charman SA; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.; Connor T; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Peat TS; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.; Avery VM; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Brisbane QLD 4111, Australia.; Bozikis YE; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Medicinal Chemistry and Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.; Yang Y; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Zhang M; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.; Monahan BJ; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; CANThera Discovery, Melbourne, VIC 3000, Australia.; Voss AK; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Thomas T; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Street IP; Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; OncologyOne Pty Ltd, Melbourne, VIC 3000, Australia; Children's Cancer Institute, Randwick, NSW 2031, Australia; University of New South Wales, Randwick, NSW 2021, Australia.; Dawson SJ; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Dawson MA; Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.; Lindeman GJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia; Parkville Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC 3050, Australia.; Davis MJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia; Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3010, Australia.; Visvader JE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.; Paul TA; Pfizer, Oncology Research & Development, San Diego, CA 92121, USA. Electronic address: thomas.a.paul@pfizer.com.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101676030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2451-9448 (Electronic) Linking ISSN: 24519448 NLM ISO Abbreviation: Cell Chem Biol Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Declaration of interests 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.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Competing Interests: Declaration of interests 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.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)