Development of a novel senolytic by precise disruption of FOXO4-p53 complex

The first senolytic agents, senescent cell-eliminating drugs Dasatinib, Quercetin, Fisetin, and Navitoclax were discovered through a hypothesis-driven approach [2Zhu Y Tchkonia T Pirtskhalava T Gower AC Ding H Giorgadze N et al.The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell. 2015; 14: 644-658Crossref PubMed Scopus (1023) Google Scholar, 3Zhu Y Tchkonia T Fuhrmann-Stroissnigg H Dai HM Ling YY Stout MB et al.Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors.Aging Cell. 2016; 15: 428-435Crossref PubMed Scopus (462) Google Scholar, 4Zhu Y Doornebal EJ Pirtskhalava T Giorgadze N Wentworth M Fuhrmann-Stroissnigg H et al.New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.Aging (Albany NY). 2017; 9: 955-963Crossref PubMed Scopus (309) Google Scholar, 5Yousefzadeh MJ Zhu Y McGowan SJ Angelini L Fuhrmann-Stroissnigg H Xu M et al.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine. 2018; 36: 18-28Summary Full Text Full Text PDF PubMed Scopus (318) Google Scholar]: Senescent cells remain viable by inactivating senescence(definition) cell anti-apoptotic pathways (SCAPs) including ephrins, PI3K isoforms, p53/p21CIP1, HIF-1α, plasminogen activated inhibitors 1 and 2, and Bcl-2 family members [[2]Zhu Y Tchkonia T Pirtskhalava T Gower AC Ding H Giorgadze N et al.The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell. 2015; 14: 644-658Crossref PubMed Scopus (1023) Google Scholar]. Therefore, the first senolytics(definition) were developed to target SCAP signalling.The work of Le et al. in EBioMedicine [[6]Le HH Cinaroglu SS Manalo EC Ors A Gomes MM Duan Sahbaz B et al.Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells.EBioMedicine. 2021 Oct 21; 73103646https://doi.org/10.1016/j.ebiom.2021.103646Summary Full Text Full Text PDF Scopus (8) Google Scholar] is based on the previously reported involvement of the FOXO4-p53 complex [[1]Baar MP Brandt RMC Putavet DA Klein JDD Derks KWJ Bourgeois BRM et al.Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.Cell. 2017; 169 (132-47 e16)Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar], a key regulator of SCAPs. FOXO4 is elevated in senescent cells and essential for maintaining viability of senescent cells by sequestering p53 in the nucleus [[1]Baar MP Brandt RMC Putavet DA Klein JDD Derks KWJ Bourgeois BRM et al.Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.Cell. 2017; 169 (132-47 e16)Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar]. Baar et al. [[1]Baar MP Brandt RMC Putavet DA Klein JDD Derks KWJ Bourgeois BRM et al.Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.Cell. 2017; 169 (132-47 e16)Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar] developed a peptide named FOXO4-DRI to disrupt the FOXO4-p53 interaction by binding to p53 and inducing p53/p21CIP1-dependent apoptosis in senescent cells (Fig. 1). In this study, Le et al. [[6]Le HH Cinaroglu SS Manalo EC Ors A Gomes MM Duan Sahbaz B et al.Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells.EBioMedicine. 2021 Oct 21; 73103646https://doi.org/10.1016/j.ebiom.2021.103646Summary Full Text Full Text PDF Scopus (8) Google Scholar] take a different approach by disrupting the FOXO4-p53 interaction with FOXO4 blocking peptides, which enable release and activation of p53. Using an atomistic model to simulate the FOXO4-p53 interaction, Le et al. identify the CR3 domain on FOXO4. A series of peptides were then designed to target high-affinity binding to the CR3 domain. Le et al. [[6]Le HH Cinaroglu SS Manalo EC Ors A Gomes MM Duan Sahbaz B et al.Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells.EBioMedicine. 2021 Oct 21; 73103646https://doi.org/10.1016/j.ebiom.2021.103646Summary Full Text Full Text PDF Scopus (8) Google Scholar] further test these putative senolytic peptides in a wide range of senescent cell types. ES2 peptides show the most potent senolytic activity among others and are 3-7 times more effective than the previously reported peptide FOXO4-DRI in both in-vitro and in-vivo studies. Le et al. [[6]Le HH Cinaroglu SS Manalo EC Ors A Gomes MM Duan Sahbaz B et al.Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells.EBioMedicine. 2021 Oct 21; 73103646https://doi.org/10.1016/j.ebiom.2021.103646Summary Full Text Full Text PDF Scopus (8) Google Scholar] highlight the safety and efficacy of ES2 in combination with the chemotherapeutic Dabrafenib as a one-two punch therapy in preclinical mouse models of melanoma.Chemotherapeutics can induce senescence in both cancer and noncancer cells, which promote cancer recurrence and accelerated aging phenotypes [[7]Wyld L Bellantuono I Tchkonia T Morgan J Turner O Foss F et al.Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies.Cancers (Basel). 2020; 12Crossref PubMed Scopus (60) Google Scholar]. Eliminating therapy-induced senescent cells (TIS) might be an effective strategy to prevent tumour relapse and reduce the long-lasting effects of the disease [[8]Coppe JP Patil CK Rodier F Sun Y Munoz DP Goldstein J et al.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoS Biology. 2008; 6: 2853-2868Crossref PubMed Scopus (2356) Google Scholar]. Given the heterogeneity of senescent cancer cells in tumour regions and TIS in normal tissues at sites distal to a tumour, the selection