Discovery of TNI-97 as a Highly Selective, Orally Bioavailable HDAC6 Inhibitor for the Treatment of Triple-Negative Breast Cancer

被引：0

作者：

Wang, Siyuan ^{[1
]}

Luo, Meidi ^{[1
]}

Xu, Qihao ^{[1
]}

Guo, Rongxian ^{[2
]}

Zhang, Wenchao ^{[1
]}

Li, Bo ^{[1
]}

Qin, Han ^{[1
]}

Wei, Leyan ^{[1
]}

Cui, Yifei ^{[1
]}

Sha, Jinyu ^{[1
]}

Shao, Shanshan ^{[1
]}

Yu, Xintian ^{[1
]}

Zhao, Linxiang ^{[1
]}

Sun, Pinghua ^{[3
]}

Bai, Changjun ^{[4
]}

Wen, Jiachen ^{[1
]}

Liu, Dan ^{[1
,4
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drugs Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[2] Henan Univ Sci & Technol, Coll Anim Sci & Technol, Lab Funct Microbiol & Anim Hlth, Luoyang 471003, Peoples R China

[3] Shihezi Univ, Inst Safflower Ind Res, Sch Pharm, Key Lab Xinjiang Phytomedicine Resource & Utilizat, Shihezi 832003, Peoples R China

[4] Qingdao Seawit Life Sci Co Ltd, Qingdao 226221, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 14期

基金：

中国国家自然科学基金;

关键词：

HISTONE DEACETYLASE INHIBITORS; BIOLOGICAL EVALUATION; DESIGN; SCAFFOLD;

D O I：

10.1021/acs.jmedchem.5c00278

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options. PANoptosis, a newly identified programmed cell death pathway, offers therapeutic strategies for TNBC. ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR+/HER2- metastatic breast cancer. However, its moderate target engagement and suboptimal selectivity may limit its clinical efficacy. In this study, a series of potent HDAC6-selective inhibitors bearing a 5-pyrazolyl-benzotriazole scaffold has been developed. Compound TNI-97 demonstrated potent HDAC6 inhibitory activity and great isoform selectivity. TNI-97 elicited PANoptotic cell death in MDA-MB-453 cell models in vitro and in vivo. TNI-97 exhibited a TGI of 91% in MDA-MB-453 CDX as monotherapy and a TGI of 92% in 4T1 CDA when combined with paclitaxel. The discovery of TNI-97 holds promise for the development of more potent HDAC6 inhibitors as PANoptotic inducers and TNBC drug candidates.

引用

页码：14333 / 14356

页数：24

共 42 条

[1] Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression [J].

Atallah, Nehal M. ;

Haque, Maria ;

Quinn, Cecily ;

Toss, Michael S. ;

Makhlouf, Shorouk ;

Ibrahim, Asmaa ;

Green, Andrew R. ;

Alsaleem, Mansour ;

Rutland, Catrin S. ;

Allegrucci, Cinzia ;

Mongan, Nigel P. ;

Rakha, Emad .

EUROPEAN JOURNAL OF CANCER, 2023, 195

[2] HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer [J].

Banik, Debarati ;

Noonepalle, Satish ;

Hadley, Melissa ;

Palmer, Erica ;

Gracia-Hernandez, Maria ;

Zevallos-Delgado, Christian ;

Manhas, Namratta ;

Simonyan, Hayk ;

Young, Colin N. ;

Popratiloff, Anastas ;

Chiappinelli, Katherine B. ;

Fernandes, Rohan ;

Sotomayor, Eduardo M. ;

Villagra, Alejandro .

CANCER RESEARCH, 2020, 80 (17) :3649-3662

[3] Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease [J].

Bianchini, Giampaolo ;

Balko, Justin M. ;

Mayer, Ingrid A. ;

Sanders, Melinda E. ;

Gianni, Luca .

NATURE REVIEWS CLINICAL ONCOLOGY, 2016, 13 (11) :674-690

[4] Discovery of N-Phenyl-5-propyl-1H-pyrazole-3-carboxamide, with Selective Inhibition and Degradation of HDAC6 for the Treatment of Acute Liver Injury [J].

Cui, Hao ;

Zhang, Guodong ;

Zhang, Liyuan ;

Sun, Shilong ;

Yang, Kang ;

Gen, Aixin ;

Wang, Penfeng ;

Wang, Hui ;

Zhou, Qing-Qing ;

Li, Hongmei ;

Chen, Yadong ;

Yao, Yuqin ;

Lu, Tao ;

Zhang, Lei ;

Zhu, Yong .

JOURNAL OF MEDICINAL CHEMISTRY, 2024, 68 (01) :531-554

[5] Dysregulation of different modes of programmed cell death by epigenetic modifications and their role in cancer [J].

Damiescu, R. ;

Efferth, T. ;

Dawood, M. .

CANCER LETTERS, 2024, 584

[6] Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer [J].

Dowling, Catriona M. ;

Hollinshead, Kate E. R. ;

Di Grande, Alessandra ;

Pritchard, Justin ;

Zhang, Hua ;

Dillon, Eugene T. ;

Haley, Kathryn ;

Papadopoulos, Eleni ;

Mehta, Anita K. ;

Bleach, Rachel ;

Lindner, Andreas U. ;

Mooney, Brian ;

Dussmann, Heiko ;

O'Connor, Darran ;

Prehn, Jochen H. M. ;

Wynne, Kieran ;

Hemann, Michael ;

Bradner, James E. ;

Kimmelman, Alec C. ;

Guerriero, Jennifer L. ;

Cagney, Gerard ;

Wong, Kwok-Kin ;

Letai, Anthony G. ;

Chonghaile, Triona Ni .

SCIENCE ADVANCES, 2021, 7 (03)

[7] Effects of α-tubulin acetylation on microtubule structure and stability [J].

Eshun-Wilson, Lisa ;

Zhang, Rui ;

Portran, Didier ;

Nachury, Maxence V. ;

Toso, Daniel B. ;

Lohr, Thomas ;

Vendruscolo, Michele ;

Bonomi, Massimiliano ;

Fraser, James S. ;

Nogales, Eva .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (21) :10366-10371

[8] Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial [J].

Fehm, Tanja ;

Cottone, Francesco ;

Dunton, Kyle ;

Andre, Fabrice ;

Krop, Ian ;

Park, Yeon Hee ;

De laurentiis, Michelino ;

Miyoshi, Yasuo ;

Armstrong, Anne ;

Borrego, Manuel Ruiz ;

Yerushalmi, Rinat ;

Duhoux, Francois P. ;

Takano, Toshimi ;

Lu, Wenjing ;

Egorov, Anton ;

Kim, Sung-Bae .

LANCET ONCOLOGY, 2024, 25 (05) :614-625

[9] HDAC6 Substrate Discovery Using Proteomics-Based Substrate Trapping: HDAC6 Deacetylates PRMT5 to Influence Methyltransferase Activity [J].

Gomes, Inosha D. ;

Ariyaratne, Udana, V ;

Pflum, Mary Kay H. .

ACS CHEMICAL BIOLOGY, 2021, 16 (08) :1435-1444

[10] Tackling triple negative breast cancer with HDAC inhibitors: 6 is the isoform! [J].

Guadagni, Anna ;

Barone, Simona ;

Alfano, Antonella Ilenia ;

Pelliccia, Sveva ;

Bello, Ivana ;

Panza, Elisabetta ;

Summa, Vincenzo ;

Brindisi, Margherita .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 279

← 1 2 3 4 5 →