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European Patent Office (19) *EP003643305A1* (11) EP 3 643 305 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 29.04.2020 Bulletin 2020/18 A61K 31/196 (2006.01) A61K 31/403 (2006.01) A61K 31/405 (2006.01) A61K 31/616 (2006.01) (2006.01) (21) Application number: 18202657.5 A61P 35/00 (22) Date of filing: 25.10.2018 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • LAEMMERMANN, Ingo GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 1170 Wien (AT) PL PT RO RS SE SI SK SM TR • GRILLARI, Johannes Designated Extension States: 2102 Bisamberg (AT) BA ME • PILS, Vera Designated Validation States: 1160 Wien (AT) KH MA MD TN • GRUBER, Florian 1050 Wien (AT) (71) Applicants: • NARZT, Marie-Sophie • Universität für Bodenkultur Wien 1140 Wien (AT) 1180 Wien (AT) • Medizinische Universität Wien (74) Representative: Loidl, Manuela Bettina et al 1090 Wien (AT) REDL Life Science Patent Attorneys Donau-City-Straße 11 1220 Wien (AT) (54) COMPOSITIONS FOR THE ELIMINATION OF SENESCENT CELLS (57) The invention relates to a composition compris- ing senescent cells. The invention further relates to an ing one or more inhibitors capable of inhibiting at least in vitro method of identifying senescent cells in a subject two of cyclooxygenase-1 (COX-1), cyclooxygenase-2 and to a method of identifying candidate compounds for (COX-2) and lipoxygenase for use in selectively eliminat- the selective elimination of senescent cells. EP 3 643 305 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 643 305 A1 2 Description al. 2018; Lewis et al. 2011; Ressler et al. 2006; Yosef et al. 2016), neurodegenerative diseases (Bussian et al. FIELD OF THE INVENTION 2018) and impaired adipogenesis (Xu et al. 2015). Fur- thermore, it was shown that clearance of senescent cells [0001] The present invention relates to the field of se- 5 attenuates the negative effects of irradiation- and chem- nolytics and provides a composition useful for the selec- otherapy-induced senescence and restores tissue func- tive elimination of senescent cells and a method of tionality (Baar et al. 2017; Chang et al. 2016; Dörr et al. screening for senolytic compounds. 2013; Pan et al. 2017). In addition to age-related diseases and disorders, cellular senescence is also associated BACKGROUND OF THE INVENTION 10 with tumor relapse following chemotherapy (Milanovic et al. 2017) and the performance of transplant organs [0002] Senescent cells were found to accumulate in (Braun et al. 2012) highlighting the potential of senolytic tissues and organs during the aging process at close therapies. proximity of age-related pathologies where they play a [0005] The list of senolytic compounds and targets critical role in the development and progression of age- 15 comprises inhibitors of the Bcl-2 family (Chang et al. related diseases and disorders. Clearance of senescent 2016; Pan et al. 2017; Yosef et al. 2016; Zhu et al. 2017; cells in mouse models using either genetic or pharma- Zhu et al. 2016), Hsp90 inhibitors (Fuhrmann-Stroissnigg cological approaches was shown to extend the health et al. 2017), dasatinib (Roos et al. 2016; Schafer et al. span, to prevent or delay the occurrence of senescence- 2017; Zhu et al. 2015), FOXO4 (Baar et al. 2017), OXR1 associated diseases and disorders and the development 20 (Zhang et al. 2018), glucose metabolism (Dörr et al. of frailty. Since then several pharmacological com- 2013), mitochondria-targeted tamoxifen (MitoTam) or re- pounds have been identified which were able to selec- duction of ATP synthase activity with oligomycin A (Hu- tively eliminate senescent cells and are generally re- backova et al. 2018) and several plant derived com- ferred to as "senolytics". pounds, such as quercetin (Roos et al. 2016; Schafer et [0003] Although cellular senescence is a tumor sup- 25 al. 2017; Zhu et al. 2015), fisetin (Zhu et al. 2017), pip- pressive mechanism which plays an important role in em- erlongumine (Wang et al. 2016a) and an alcoholic extract bryonic development (Muñoz-Espín et al. 2013) and of solidago virgaurea (Lämmermann et al. 2018). wound healing (Demaria et al. 2014), the chronic accu- [0006] However, many of the reported senolytics like mulation of senescent cells in organs and tissue during navitoclax and dasatinib have serious side effects and the aging process is believed to be a major driving force 30 most senolytics are not universally effective in all cell for the development and progression of age-related dis- types. Therefore, there is a strong need in the field for eases and disorders. Senescent cells are terminally improved senolytics with less severe side effects and growth arrested either via the p53-p21CIP1 or via the broad range of applications. p16INK4a-Rb axis, accumulate senescence-associated β-galactosidase activity (SA-β-gal) and display a typical 35 SUMMARY OF THE INVENTION morphology (Campisi and d’Adda di Fagagna 2007). When chronically present, they negatively affect the sur- [0007] It is the objective of the present invention, to rounding tissue by secreting a pro-tumorigenic and pro- provide a composition capable of efficiently eliminating inflammatory mixture of cytokines, growth factors and senescent cells. It is a further objective of the present proteases (Acosta et al. 2013; Coppé et al. 2010; Krtolica 40 invention to provide a method to screen for compounds et al. 2001) termed the senescence-associated secretory useful for the selective elimination of senescent cells. phenotype (SASP). [0008] The problem is solved by the present invention. [0004] Genetic mouse models using the p16INK4a pro- [0009] The inventors have shown that senescent cells moter to visualize and selectively eliminate p16INK4a pos- comprise an altered lipid metabolism, which can be ex- itive cells convincingly demonstrated that senescent cells 45 ploited to selectively eliminate senescent cells. In partic- accumulate during the aging process in vivo and that the ular, lyso PC is upregulated in senescent cells, indicating clearance of p16INK4a positive cells increases the health an increased formation of arachidonic acid. Arachidonic span and impairs the development and progression of acid is metabolized to eicosanoids by lipoxygenases and senescence-associated diseases and disorders (Baker cyclooxygenases, thereby preventing cell death due to et al. 2016; Baker et al. 2011). There is compelling evi- 50 high intracellular levels of arachidonic acid. Accordingly, dence for a causal relationship between senescent cells inhibition of lipoxygenases or cyclooxygenases leads to and several age-related diseases and disorders, such as an increase in arachidonic acid in senescent cells and, atherosclerosis (Childs et al. 2016; Roos et al. 2016), thus, to selective elimination of senescent cells. idiopathic pulmonary fibrosis (Lehmann et al. 2017; [0010] According to the invention there is provided a Schafer et al. 2017), osteoporosis (Farr et al. 2017; Zhu 55 composition comprising one or more inhibitors capable et al. 2015), post-traumatic osteoarthritis (Jeon et al. of inhibiting at least two of cyclooxygenase-1 (COX-1), 2017), renal aging (Schmitt and Melk 2017; Valentijn et cyclooxygenase-2 (COX-2) and lipoxygenase, for use in al. 2018), skin aging (Baar et al. 2017; Lämmermann et selectively eliminating senescent cells. 2 3 EP 3 643 305 A1 4 [0011] Specifically, the one or more inhibitors are spe- fluriprofen methyl ester, metamizole, nitroaspirin, melox- cific inhibitors of COX-1 and/or COX-2. icam, flufenamic acid, oxaprozin, tiaprofenic acid, mag- [0012] Specifically, the composition provided herein nesium salicylate, diethylcarbamazine, lornoxicam, car- comprises one or more inhibitors and is capable of inhib- profen, phenylbutazone, nepafenac, antipyrine, antrafe- iting the enzymatic activity of at least two enzymes se- 5 nine, choline magnesium trisalicylate, triflusal, niflumic lected from the group consisting of COX-1, COX-2 and acid, dexibuprofen, aceclofenac, acemetacin, droxicam, lipoxygenase. loxoprofen, tolfenamic acid, dexketoprofen, talniflumate, [0013] According to a specific embodiment, the com- propacetamol, trolamine salicylate, phenyl salicylate, position provided herein comprises at least two inhibitors. bufexamac, glycol salicylate, menthyl salicylate, FK-506, Specifically, the composition provided herein comprises 10 lenalidomide, rofecoxib, valdecoxib, cimicoxib, chlorphe- at least one COX-1 or COX-2 inhibitor and at least one nesin, clodronic acid, seliciclib, drospirenone, triamci- lipoxygenase inhibitor. Specifically, the composition nolone, pomalidomide, parecoxib, firocoxib, aclofenac, comprises at least one COX-1 inhibitor and at least one adapalene, thalidomide, etoricoxib, robenacoxib, asaral- COX-2 inhibitor. Specifically, the composition provided dehyde, zaltoprofen, deracoxib, dexamethasone, pran- comprises a cyclooxygenase inhibitor, selected from the 15 oprofen, amfenac sodium monohydrate, ampiroxicam, group consisting of COX-1 inhibitor, COX-2 inhibitor and NS-398, bismuth subsalicylate, diclofenac diethylamine, COX-1/COX-2 inhibitor, and a lipoxygenase inhibitor. trometamol, rutaecarpine, salicin, fenbufen, xanthohu- Specifically, the composition provided herein comprises mol, flunixin meglumin and nimesulide. at least one COX-1 inhibitor and at least one lipoxygen- [0019] Specifically, one or more inhibitors comprised ase inhibitor, or at least one COX-2 inhibitor and at least 20 in the composition provided herein are lipoxygenase one lipoxygenase inhibitor, or at least one COX-1/COX-
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