Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

Leaver David J.; Cleary Benjamin; Nghi Nguyen; Priebbenow Daniel L.; Lagiakos H. Rachel; Sanchez Julie; Xue Lian; Huang Fei; Sun Yuxin; Mujumdar Prashant; Mudududdla Ramesh; Varghese Swapna; Teguh Silvia; Charman Susan A.; White Karen L.; Katneni Kasiram; Cuellar Matthew; Strasser Jessica M.; Dahlin Jayme L.; Walters Michael A.; Street Ian P.; Monahan Brendon J.; Jarman Kate E.; Sabroux Helene Jousset; Falk Hendrik; Chung Matthew C.; Hermans Stefan J.; Parker Michael W.; Thomas Tim; Baell Jonathan B.

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Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

机译：将苯甲酰磺酰肼发现为组蛋白乙酰转移酶KAT6A的有效抑制剂

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A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 HM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 /mu M). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool,

机译：组蛋白乙酰转移酶KAT6A的抑制剂的高通量筛网导致鉴定抑制KAT6A的芳基磺酰肼衍生物（CTX-0124143），IC50为1.0 hm。制定结构 - 活性关系和药用化学优化导致WM-8014（97）的发现，高效的KAT6A（IC50 = 0.008 / mu m）。 WM-8014与乙酰-CoA（AC-COA）竞争，X射线晶体分析证明与AC-CoA结合位点的结合。通过抑制KAT6a活性，WM-8014诱导细胞衰老，代表一种独特的药理学工具，

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《Journal of Medicinal Chemistry》 |2019年第15期|共14页
作者
Leaver David J.; Cleary Benjamin; Nghi Nguyen; Priebbenow Daniel L.; Lagiakos H. Rachel; Sanchez Julie; Xue Lian; Huang Fei; Sun Yuxin; Mujumdar Prashant; Mudududdla Ramesh; Varghese Swapna; Teguh Silvia; Charman Susan A.; White Karen L.; Katneni Kasiram; Cuellar Matthew; Strasser Jessica M.; Dahlin Jayme L.; Walters Michael A.; Street Ian P.; Monahan Brendon J.; Jarman Kate E.; Sabroux Helene Jousset; Falk Hendrik; Chung Matthew C.; Hermans Stefan J.; Parker Michael W.; Thomas Tim; Baell Jonathan B.;
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Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Nanjing Tech Univ Sch Pharmaceut Sci 30 South Puzhu Rd Nanjing 211816 Jiangsu Peoples R China;

Nanjing Tech Univ Sch Pharmaceut Sci 30 South Puzhu Rd Nanjing 211816 Jiangsu Peoples R China;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Med Chem Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Ctr Drug Candidate Optimisat Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Ctr Drug Candidate Optimisat Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Monash Univ Ctr Drug Candidate Optimisat Monash Inst Pharmaceut Sci Parkville Campus 381 Royal Parade Parkville Vic 3052 Australia;

Univ Minnesota Inst Therapeut Discovery &

Dev 717 Delaware St SE Minneapolis MN 55455 USA;

Univ Minnesota Inst Therapeut Discovery &

Dev 717 Delaware St SE Minneapolis MN 55455 USA;

Brigham &

Womens Hosp Dept Pathol 75 Francis St Boston MA 02115 USA;

Univ Minnesota Inst Therapeut Discovery &

Dev 717 Delaware St SE Minneapolis MN 55455 USA;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

St Vincents Inst Med Res ACRF Rat Drug Discovery Ctr Fitzroy Vic 3065 Australia;

St Vincents Inst Med Res ACRF Rat Drug Discovery Ctr Fitzroy Vic 3065 Australia;

St Vincents Inst Med Res ACRF Rat Drug Discovery Ctr Fitzroy Vic 3065 Australia;

Walter &

Eliza Hall Inst Med Res 1G Royal Parade Parkville Vic 3052 Australia;

Nanjing Tech Univ Sch Pharmaceut Sci 30 South Puzhu Rd Nanjing 211816 Jiangsu Peoples R China;

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正文语种 eng
中图分类药学;
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1. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A [J] . Leaver David J., Cleary Benjamin, Nghi Nguyen, Journal of Medicinal Chemistry . 2019,第15期

机译：将苯甲酰磺酰肼发现为组蛋白乙酰转移酶KAT6A的有效抑制剂
2. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors [J] . Yang Yaxi, Zhang Rukang, Li Zhaojun, Journal of Medicinal Chemistry . 2020,第3期

机译：发现高效，选择性和口服有效的P300 / CBP组氨基乙酰转移酶抑制剂
3. Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor [J] . Wilson Jonathan E., Patel Gaurav, Patel Chirag, ACS medicinal chemistry letters . 2020,第6期

机译：CPI-1612的发现：有效，选择性和口服生物可利用的EP300 / CBP组氨酸乙酰转移酶抑制剂
4. Design and Discovery of Diarylpyridines and Diarylanilines as Novel Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors [C] . Bingjie Qin, Xingtao Tian, Xingkai Jiang, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：二芳基吡啶和二芳基苯胺作为新型有效的非核苷HIV-1逆转录酶抑制剂的设计和发现
5. P27 as a molecular target for cancer therapeutics: Discovering small molecule inhibitors of p27 proteolysis and structure-activity relationship and mechanistic studies of largazole, a potent inhibitor of histone deacetylase . [D] . Ungermannova, Dana. 2010

机译：P27作为癌症治疗的分子靶标：发现p27蛋白水解和结构活性关系的小分子抑制剂以及组蛋白脱乙酰基酶的有效抑制剂largazole的机理研究。
6. Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding [O] . Deguan Lv, Feng Jia, Yanli Hou, -1

机译：组蛋白乙酰转移酶KAT6A通过TRIM24结合上调PI3K / AKT信号传导
7. Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A [O] . -1

机译：将苯甲酰磺酰肼发现为组蛋白乙酰转移酶KAT6A的有效抑制剂

Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

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