发现一种高效、选择性、口服生物可利用的 KAT6A/B 组蛋白乙酰转移酶抑制剂，可有效对抗 KAT6A 高 ER+ 乳腺癌,Cell Chemical Biology

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发现一种高效、选择性、口服生物可利用的 KAT6A/B 组蛋白乙酰转移酶抑制剂，可有效对抗 KAT6A 高 ER+ 乳腺癌
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2023-08-08 , DOI: 10.1016/j.chembiol.2023.07.005
Shikhar Sharma ₁ , Chi-Yeh Chung ₁ , Sean Uryu ₁ , Jelena Petrovic ₁ , Joan Cao ₁ , Amanda Rickard ₁ , Nataliya Nady ₁ , Samantha Greasley ₁ , Eric Johnson ₁ , Oleg Brodsky ₁ , Showkhin Khan ₁ , Hui Wang ₁ , Zhenxiong Wang ₁ , Yong Zhang ₁ , Konstantinos Tsaparikos ₁ , Lei Chen ₁ , Anthony Mazurek ₁ , John Lapek ₁ , Pei-Pei Kung ₁ , Scott Sutton ₁ , Paul F Richardson ₁ , Eric C Greenwald ₁ , Shinji Yamazaki ₁ , Rhys Jones ₁ , Karen A Maegley ₁ , Patrick Bingham ₁ , Hieu Lam ₁ , Alexandra E Stupple ₂ , Aileen Kamal ₃ , Anderly Chueh ₄ , Anthony Cuzzupe ₅ , Benjamin J Morrow ₆ , Bin Ren ₇ , Catalina Carrasco-Pozo ₈ , Chin Wee Tan ₉ , Dharmesh D Bhuva ₉ , Elizabeth Allan ₄ , Elliot Surgenor ₃ , François Vaillant ₉ , Havva Pehlivanoglu ₃ , Hendrik Falk ₁₀ , James R Whittle ₉ , Janet Newman ₁₁ , Joseph Cursons ₃ , Judy P Doherty ₁₂ , Karen L White ₁₃ , Laura MacPherson ₁₂ , Mark Devlin ₁₄ , Matthew L Dennis ₇ , Meghan K Hattarki ₁₁ , Melanie De Silva ₄ , Michelle A Camerino ₁₃ , Miriam S Butler ₁₄ , Olan Dolezal ₇ , Patricia Pilling ₁₁ , Richard Foitzik ₁₅ , Paul A Stupple ₂ , H Rachel Lagiakos ₁₃ , Scott R Walker ₁₆ , Soroor Hediyeh-Zadeh ₉ , Stewart Nuttall ₇ , Sukhdeep K Spall ₄ , Susan A Charman ₁₃ , Theresa Connor ₁₄ , Thomas S Peat ₇ , Vicky M Avery ₈ , Ylva E Bozikis ₁₃ , Yuqing Yang ₉ , Ming Zhang ₄ , Brendon J Monahan ₁₇ , Anne K Voss ₉ , Tim Thomas ₉ , Ian P Street ₁₈ , Sarah-Jane Dawson ₁₂ , Mark A Dawson ₁₂ , Geoffrey J Lindeman ₁₉ , Melissa J Davis ₂₀ , Jane E Visvader ₉ , Thomas A Paul ₁

Affiliation

Pfizer, Oncology Research & Development, San Diego, CA 92121, USA.
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.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
SYNthesis Med Chem (Australia) Pty Ltd, Bio21 Institute, 30 Flemington Road, Parkville, VIC 3052, Australia.
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.
Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.
Cancer Therapeutics CRC, Melbourne, VIC 3000, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Brisbane QLD 4111, 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.
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.
Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia.
Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3052, Australia.
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.
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.
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.
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.
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.
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.
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.
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.

KAT6A 及其旁系同源物 KAT6B 是组蛋白赖氨酸乙酰转移酶 (HAT)，可乙酰化组蛋白 H3K23，并在多种肿瘤类型中发挥致癌作用，包括乳腺癌，其中 KAT6A 经常被扩增/过表达。然而，通过药物靶向 KAT6A 来实现治疗效果一直是一个挑战。在这里，我们描述了一种高效、选择性和口服生物可利用的 KAT6A/KAT6B 抑制剂 CTx-648 (PF-9363) 的鉴定，该抑制剂源自苯并异恶唑系列，证明其抗肿瘤活性与 KAT6A 过表达乳腺中的 H3K23Ac 抑制相关癌症。转录和表观遗传分析研究表明，在 ER 阳性 (ER+) 乳腺癌中，与 CTx-648 抗肿瘤活性相关的雌激素信号传导、细胞周期、Myc 和干细胞通路相关基因的 RNA Pol II 结合减少和下调。CTx-648 治疗可在 ER+ 乳腺癌体内模型（包括内分泌治疗难治性模型）中产生有效的肿瘤生长抑制作用，凸显了在 ER+ 乳腺癌中靶向 KAT6A 的潜力。

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更新日期：2023-08-08

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