RSK inhibitors as potential anticancer agents: Discovery, optimization, and challenges

被引:10
作者
Sun, Ying [1 ,2 ,3 ,4 ,5 ]
Tang, Lichao [6 ]
Wu, Chengyong [1 ,4 ,5 ]
Wang, Jiaxing [7 ]
Wang, Chengdi [1 ]
机构
[1] Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Dept Resp & Crit Care Med,Targeted Tracer Res & De, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Natl Clin Res Ctr Geriatr,Dept Resp & Crit Care Me, Chengdu 610041, Sichuan, Peoples R China
[3] Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Canc Ctr,Dept Resp & Crit Care Med, Chengdu 610041, Sichuan, Peoples R China
[4] Sichuan Univ, West China Hosp, Precis Med Key Lab Sichuan Prov, Chengdu 610041, Sichuan, Peoples R China
[5] Sichuan Univ, West China Hosp, Precis Med Res Ctr, Chengdu 610041, Sichuan, Peoples R China
[6] Northwestern Univ, McCormick Sch Engn, Dept Biomed Engn, Evanston, IL 60208 USA
[7] Univ Tennessee, Coll Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, Memphis, TN 38163 USA
关键词
RSK; Inhibitors; Cancer; Structure-activity relationship; BOX BINDING PROTEIN-1; OVARIAN-CANCER CELLS; N-TERMINAL DOMAIN; KINASE RSK; IN-VITRO; 5A-CARBASUGAR ANALOGS; BIOLOGICAL EVALUATION; HSP90; INHIBITOR; SL0101; PHOSPHORYLATION;
D O I
10.1016/j.ejmech.2023.115229
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Ribosomal S6 kinase (RSK) family is a group of serine/threonine kinases, including four isoforms (RSK1/2/3/4). As a downstream effector of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway, RSK participates in many physiological activities such as cell growth, proliferation, and migration, and is intimately involved in tumor occurrence and development. As a result, it is recognized as a potential target for anti-cancer and anti -resistance therapies. There have been several RSK inhibitors discovered or designed in recent decades, but only two have entered clinical trials. Low specificity, low selectivity, and poor pharmacokinetic properties in vivo limit their clinical translation. Published studies performed structure optimization by increasing interaction with RSK, avoiding hydrolysis of pharmacophores, eliminating chirality, adapting to binding site shape, and becoming prodrugs. Besides enhancing efficacy, the focus of further design will move towards selectivity since there are functional differences among RSK isoforms. This review summarized the types of cancers associated with RSK, along with the structural characteristics and optimization process of the reported RSK inhibitors. Furthermore, we addressed the importance of RSK inhibitors' selectivity and discussed future drug development directions. This review is expected to shed light on the emergence of RSK inhibitors with high potency, specificity, and selectivity.
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收藏
页数:18
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共 130 条
[1]   The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase-1 beta (Rsk-2) and p70 S6 kinase [J].
Alessi, DR .
FEBS LETTERS, 1997, 402 (2-3) :121-123
[2]   Potential Antitumor Agents.: 42.: New antitumor imidazo[2,1-b]thiazole guanylhydrazones and analogues' [J].
Andreani, Aldo ;
Burnelli, Silvia ;
Granaiola, Massimiliano ;
Leoni, Alberto ;
Locatelli, Alessandra ;
Morigi, Rita ;
Rambaldi, Mirella ;
Varoli, Lucilla ;
Calonghi, Natalia ;
Cappadone, Concettina ;
Farruggia, Giovanna ;
Zini, Maddalena ;
Stefanelli, Claudio ;
Masotti, Lanfranco ;
Radin, Norman S. ;
Shoemaker, Robert H. .
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :809-816
[3]   Imidazo[2,1-b]thiazole guanylhydrazones as RSK2 inhibitors [1] [J].
Andreani, Aldo ;
Granaiola, Massimiliano ;
Leoni, Alberto ;
Locatelli, Alessandra ;
Morigi, Rita ;
Rambaldi, Mirella ;
Varoli, Lucilla ;
Lannigan, Deborah ;
Smith, Jeff ;
Scudiero, Dominic ;
Kondapaka, Sudhir ;
Shoemaker, Robert H. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2011, 46 (09) :4311-4323
[4]  
Asakura N., 2021, INT J MOL SCI, P22
[5]   Drosophila RSK Influences the Pace of the Circadian Clock by Negative Regulation of Protein Kinase Shaggy Activity [J].
Beck, Katherina ;
Hovhanyan, Anna ;
Menegazzi, Pamela ;
Helfrich-Foerster, Charlotte ;
Raabe, Thomas .
FRONTIERS IN MOLECULAR NEUROSCIENCE, 2018, 11
[6]   First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer. [J].
Beeram, Muralidhar ;
Chalasani, Pavani ;
Wang, Judy S. ;
Mina, Lida A. ;
Shatsky, Rebecca Arielle ;
Trivedi, Meghna S. ;
Wesolowski, Robert ;
Hurvitz, Sara A. ;
Han, Hyo S. ;
Patnaik, Amita ;
Pambid, Mary Rose ;
Jayanthan, Aarthi ;
Huynh, My-My ;
Los, Gerrit ;
Dunn, Sandra Elaine ;
Dorr, Andrew .
JOURNAL OF CLINICAL ONCOLOGY, 2021, 39 (15)
[7]  
Ben Djoudi Ouadda Ali, 2018, Oncotarget, V9, P11646, DOI 10.18632/oncotarget.24126
[8]   A large-scale RNAi screen in human cells identifies new components of the p53 pathway [J].
Berns, K ;
Hijmans, EM ;
Mullenders, J ;
Brummelkamp, TR ;
Velds, A ;
Heimerikx, M ;
Kerkhoven, RM ;
Madiredjo, M ;
Nijkamp, W ;
Weigelt, B ;
Agami, R ;
Ge, W ;
Cavet, G ;
Linsley, PS ;
Beijersbergen, RL ;
Bernards, R .
NATURE, 2004, 428 (6981) :431-437
[9]   RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer [J].
Bignone, P. A. ;
Lee, K. Y. ;
Liu, Y. ;
Emilion, G. ;
Finch, J. ;
Soosay, A. E. R. ;
Charnock, F. M. L. ;
Beck, S. ;
Dunham, I. ;
Mungall, A. J. ;
Ganesan, T. S. .
ONCOGENE, 2007, 26 (05) :683-700
[10]   Indole RSK inhibitors. Part 1: Discovery and initial SAR [J].
Boyer, Stephen J. ;
Burke, Jennifer ;
Guo, Xin ;
Kirrane, Thomas M. ;
Snow, Roger J. ;
Zhang, Yunlong ;
Sarko, Chris ;
Soleymanzadeh, Lida ;
Swinamer, Alan ;
Westbrook, John ;
DiCapua, Frank ;
Padyana, Anil ;
Cogan, Derek ;
Gao, Amy ;
Xiong, Zhaoming ;
Madwed, Jeffrey B. ;
Kashem, Mohammed ;
Kugler, Stanley ;
O'Neill, Margaret M. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (01) :733-737