WO2021092061A1 - Polythérapie pour le traitement de maladies associées à la sénescence - Google Patents
Polythérapie pour le traitement de maladies associées à la sénescence Download PDFInfo
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- WO2021092061A1 WO2021092061A1 PCT/US2020/058944 US2020058944W WO2021092061A1 WO 2021092061 A1 WO2021092061 A1 WO 2021092061A1 US 2020058944 W US2020058944 W US 2020058944W WO 2021092061 A1 WO2021092061 A1 WO 2021092061A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
Definitions
- senescent cells cells that have lost replicative capacity (known as senescent cells) remain in the tissue, where they trigger, mediate, or exacerbate certain diseases, often a consequence of age-related conditions.
- the senescent cells are thought to produce a constellation of secreted factors that act as cytokines, pro-inflammatory agents, and other compounds that cause degree progression and adverse symptoms, such as, for example, fibrosis.
- cytokines cytokines
- pro-inflammatory agents and other compounds that cause degree progression and adverse symptoms, such as, for example, fibrosis.
- the technology described in this patent application represents a further advance in the development of senolytic agents for eliminating senescent cells and resolving senescence-associated diseases.
- This invention is based on the discovery that a novel combination of senolytics can effectively eliminate senescent cells as well as increase the potency of the therapy.
- Combining a Bcl-XL inhibitor with a novel Mcl-1 inhibitor in accordance with this invention increases the ability of the Bcl-XL inhibitor to remove senescent cells from the site of an adverse condition — not just additively, but synergistically.
- Some Bcl-XL and Mcl-1 inhibitors that are ineffective on their own when used in vitro and/or in vivo may be combined to form a potent duo that is effective for treatment of a wide range of conditions that are thought to be mediated by senescent cells.
- the technology provided in this disclosure represents an important advance in the science of senolytic medicine in several ways.
- effective combinations of the two senolytics of the invention has the ability to eliminate senescent cells in particular tissues that may not be easily amenable to treatment via a single senolytic agent.
- the synergistic effect of certain Bcl-XL and Mcl-1 inhibitor combinations of the invention means that the tissue burden of the combined therapy (in terms of molecular mass) is substantially reduced. This has the potential benefit of increasing the therapeutic range for a particular target, increasing the potency against target cells while decreasing the risk of side effects.
- Combination senolytic therapies are described and exemplified herein comprising Bcl-XL inhibitors and Mcl-1 inhibitors. Contacting senescent cells in vitro or in vivo with the senolytic combinations of the invention selectively eliminates such cells.
- the inhibitors can be used for administration to a target tissue in a subject having an age-related senescence-associated disease, thereby selectively eliminating senescent cells in or around the tissue and relieving one or more symptoms or signs of the conditions.
- This disclosure provides methods for treating a senescence-associated disease comprising administering to a subject in need thereof a combination of a Bcl-XL inhibitor and an Mcl-1 inhibitor, wherein the Mcl-1 inhibitor is a compound of Formula M-IIIb: wherein: Z 2 is selected from -OR 1 , and -NHSO 2 R 3 ; R 1 is selected from H, and -(CH 2 ) n OP(O)(OR 2 ) 2 ; R 2 is selected from H, and C (1-6) alkyl; R 3 is selected from C (1-6) alkyl, substituted C (1-6) alkyl, aryl, and substituted aryl; Y 1 is selected from halogen, nitrile, and C (1-6) alkyl; X 2 is selected from O, S, NR 4b , and SO 2 ; X 3 is selected from S and CH 2 ; X 1 is selected from C (1-6)
- the disclosed methods for treating a senescence-associated disease include Bcl-XL inhibitors described by the Formula (B-IIa): wherein: X 2 is –COOH; or –SO 2 CH 3 ; X 3 is –SO 2 CF 3 ; –SO 2 CH 3 ; or –NO 2 ; X 5 is –F or –H; and R6 is selected from –OR7, , or ; and R7 is –H, –P(O)(OH) 2 , or –(CnH2n)P(O)(OH) 2 (where n is 1 to 4 or 1 to 8), or a pharmaceutically acceptable salt thereof.
- Exemplary Bcl-XL inhibitors of Formula (B-IIb) include the following structure: [0013]
- the disclosed methods for treating a senescence-associated disease include Bcl-XL inhibitors described by the Formula (B-IIIb): wherein: R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ; n is 1 or 2; Z 6 is selected from O, CHC(O)R 18 , and CH(CH 2 ) p R 18 wherein p is 0-6 and each R 18 is independently –OR, –N(R) 2 , –OP( ⁇ O)(OH) 2 , and –OP( ⁇ O)(OR) 2 wherein each R is independently H, alkyl or substituted alkyl (e.g., a C 1-4 alkyl such as ethyl or tert-butyl); R 14 and R 16 are independently hydrogen or halogen; and R 17 is selected from SO 2 R 52 , COR
- Exemplary Bcl-XL inhibitors of Formula (B-IIIb) include the following structures: [0015] Sometimes in the disclosed methods for treating a senescence-associated disease, the combination of a Bcl-XL inhibitor and an Mcl-1 inhibitor has a synergy coefficient ( ⁇ ) greater than 10, greater than 20, greater than 30, greater than 40, greater than 50, greater than 60, or greater than 70. [0016] Sometimes in the disclosed methods for treating a senescence-associated disease, the combination of a Bcl-XL inhibitor and an Mcl-1 inhibitor has a synergy coefficient ( ⁇ ) from 10-100, from 20-70, from 30-60, or from 40-50.
- the Bcl- XL inhibitor and Mcl-1 inhibitor selectively kill senescent cells.
- the disclosed methods for treating a senescence-associated disease include, senescent cells that are senescent endothelial cells, senescent fibroblasts, senescent epithelial cells, senescent mesenchymal cells, senescent chondrocytes, or senescent synoviocytes.
- the senescence-associated disease is a pulmonary disease.
- the pulmonary disease is selected from, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, and emphysema.
- IPF idiopathic pulmonary fibrosis
- COPD chronic obstructive pulmonary disease
- asthma cystic fibrosis
- bronchiectasis bronchiectasis
- emphysema emphysema.
- the senescence-associated disease is a hepatic disease.
- the hepatic disease is selected from, viral hepatitis, alcoholic hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, ⁇ 1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), acute-on chronic liver failure (ACLF), and hepatic encephalopathy (HE).
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- ACLF acute-on chronic liver failure
- HE hepatic encephalopathy
- the senescence-associated disease is atherosclerosis.
- the senescence-associated disease is osteoarthritis.
- the senescence-associated disease is an ocular disease.
- the ocular disease is age-related macular degeneration, retinoblastoma, glaucoma, or diabetic retinopathy.
- the senescence-associated disease is a pulmonary disease, osteoarthritis, or an ocular disease, and the Bcl-XL inhibitor, and the Mcl-1 inhibitor are locally administered to the affected tissue or organ.
- the senescence-associated disease is a hepatic disease or atherosclerosis, and the Bcl-XL inhibitor, and the Mcl-1 inhibitor are administered systemically.
- This disclosure also provides the use of a Bcl-XL inhibitor and an Mcl-1 inhibitor for the manufacture of a combination medicament for the treatment of a senescence-associated disease in a subject, wherein the Mcl-1 inhibitor is a compound of Formula (M-IIIb), e.g., as described herein.
- the Mcl-1 inhibitor is a compound of Formula (M-IIIb), e.g., as described herein.
- Exemplary Bcl-XL inhibitors for use in the manufacture of a combination medicament include compounds of Formula (B-IIa), e.g., as described herein.
- Exemplary Bcl-XL inhibitors for use in the manufacture of a combination medicament include compounds of Formula (B-IIIb), e.g., as described herein.
- This disclosure also provides pharmaceutical compositions comprising an Mcl-1 inhibitor having the compound of structure (M1-1): in combination with a Bcl-XL inhibitor compound of Formula (B-IIa) or (B-IIIb), e.g., as described herein.
- Mcl-1 inhibitor having the compound of structure (M1-1): in combination with a Bcl-XL inhibitor compound of Formula (B-IIa) or (B-IIIb), e.g., as described herein.
- FIG.1 panels A-D demonstrate the ability to induce senescence in primary human epithelial cells by irradiation, where FIG.
- panel A demonstrates normal, non-senescent cells (NsC), as validated by the detection of senescence ⁇ -galactosidase staining (FIG. 1, panels B-C) and by qPCR detecting p16 (FIG.1, panel D). See Example 1.
- FIG.2 panels A-C show in small airway lung epithelial cells, three different Bcl-XL inhibitors (Compound B-39-1 in FIG.2, panel A; Compound B-39-2 in FIG.2, panel B; Compound 5 in FIG.2, panel C) selectively eliminate senescent cells over non-senescent cells; further, the senolytic potency of all three tested Bcl-XL inhibitors was greatly enhanced by the addition of an Mcl-1 inhibitor. See Example 5.
- FIG.3, panels A-B show dose-responses of biochemical target engagement using Bcl-XL and Mcl-1 inhibitors (Compound B-39-1 (“Compound 39”), Compound B-39-2 (“Compound Y”) and Compound 5 in FIG.
- FIG.4 panels A-B show dose-responses of cellular target engagement using Bcl-XL and Mcl- 1 inhibitors (Compound B-39-1 (“Compound 39”), Compound B-39-2 (“Compound Y”) and Compound 5 in FIG.4, panel A; Compound M1-1 (“Compound M-1”) in FIG.4, panel B), indicating potent blocking of cell endogenous Bcl-XL/BIM or Mcl-1/BIM interactions (both pEC50 > 8). See Example 7.
- FIG. 5, panels A-C show a synergy determination of senolytic combinations of Bcl-XL inhibitors (Compound 5 in FIG.5, panel A; Compound B-39-1 in FIG.5, panel B; and Compound B-39-2 in FIG.5, panel C) and the Mcl-1 inhibitor Compound M1-1 on senescent epithelial cells.
- Bcl-XL inhibitors Compound 5 in FIG.5, panel A; Compound B-39-1 in FIG.5, panel B; and Compound B-39-2 in FIG.5, panel C
- Mcl-1 inhibitor Compound M1-1 on senescent epithelial cells See Example 8.
- Senescent cells are characterized as cells that no longer have replicative capacity, but remain in the tissue of origin, eliciting a senescence-associated secretory phenotype (SASP). Senescent cells accumulate with age, which is why disease conditions mediated by senescent cells occur more frequently in older adults.
- SASP senescence-associated secretory phenotype
- Mcl-1 Inhibitors This section provides novel compounds that constitute a means for inhibiting Mcl-1. They are suitable for use as senolytic agents in combination with Bcl-XL family inhibitors to provide an enhanced senolytic potency to promote the selective apoptosis of senescent cells, according to this invention.
- Mcl-1 inhibitors includes, for example, macrocyclic compounds that have the following structure (M-I): (M-I) wherein: Z 1 is selected from -C(O)OR 1 , -C(S)OR 1 , -C(O)SR 1 , -C(S)SR 1 , -C(O)N(R 2 )SO 2 (R 3 ), -OR 1 , -SR 1 , N(R 2 ) 2 , C(O)R 1 , -OCOR 1 , -C(O)N(R 2 ) 2 , -N(R 2 )C(O)R 1 , -N(R 2 )C(O)N(R 2 ) 2 , -N(R 2 )SO 2 R 3 , -SO 2 R 3 and - SO 2 N(R 2 ) 2 ; R 1 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
- R 1 -R 10 , Y 1 -Y 3 and X 1 in a compound of formula (M-I) that include a substituted alkyl, a substituted alkoxy, substituted cycloalkyl, substituted alkenyl, substituted cycloalkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted heteroaryl, or a substituted alkylakoxy the substituent can be one to three R b groups.
- Each R b group may be the same or different and optionally chosen from C (1-6) alkyl (optionally substituted with one to three R c groups), hydroxyl, C (1-6) alkoxy (e.g., OCH3, or OCF3), -(CR 4 )mOR 4a , -(CR 4 )mcycloalkyl-(OR 4a )p, -(CR 4 )mheterocycloalkyl-(OR 4a )p, -(CR 4 )maryl- (OR 4a )p, -(CR 4 )mheteroaryl-(OR 4a )p, and -(CR 4 )mN(R a ) 2 , halogen, nitrile, acyl, carboxyl, -OP(O)(OR a ) 2 , and -(CR 4 )mOP(O)(OR a ) 2 , where each R a may be the same or different and is chosen from hydrogen, C
- the substituent can be one to three R b groups selected from C (1-6) alkyl, halogen, nitrile, hydroxyl, C (1-6) alkoxy, amino, acyl, carboxy, -OP(O)(OR a ) 2 , and - C (1-6) alkyl-OP(O)(OR a ) 2 , where each R a may be the same or different and is chosen from H, and C (1-6) alkyl.
- This disclosure includes macrocyclic compounds where at least one of Z 2 -Z 4 or Z 5 -Z 7 is N, such that the macrocycle includes at least one 5-membered heterocycle (e.g., a pyrrole, a pyrazole or an imidazole).
- the macrocycle includes a 5-membered pyrazole groups.
- the macrocycle includes a 5-membered pyrrole group or an imidazole group.
- macrocyclic compounds where at least one of Z 2 -Z 4 is N, and at least one of Z 5 -Z 7 is N, such that the macrocycle includes two 5-membered heterocycles (e.g., a pyrrole, a pyrazole or an imidazole).
- two of Z 2 -Z 4 are N, and two of Z 5 -Z 7 are N.
- the macrocycle includes two 5-membered pyrazole groups.
- the macrocycle includes two 5-membered imidazole groups.
- This disclosure includes macrocyclic compounds with Z 2 being CR 4 ; and Z 3 and Z 4 being N.
- Z 2 is CR 4 , where R 4 is alkyl, such as C (1-6) alkyl.
- Z 2 and Z 3 are N, and Z 4 is CR 4 .
- This disclosure includes macrocyclic compounds with R 5 and R 6 being N and R 7 being CR 4 .
- Z 7 is CR 4 , where R 4 is H.
- R 7 and R 6 are N and R 5 is CR 4 .
- R 7 and R 5 are N and R 6 is CR 4 .
- the macrocyclic compound of Formula (M-I) can be further described by Formula (M-Ia):
- Z 1 is selected from -C(O)OR 1 , -C(O)N(R 2 )SO 2 (R 3 ), -OR 1 , -C(O)R 1 , -C(O)N(R 2 ) 2 ;
- R 1 is selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, and - (CH 2 ) n OP(O)(OR 2 ) 2 ;
- R 2 is selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
- R 3 is selected from C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
- X 1 is selected from C (1-6) alkyl, substituted C
- R 1 -R 5 , R 8 -R 10 , Y 1 -Y 3 and X 1 in a compound of formula (M-Ia) that include a substituted C (1-6) alkyl, a substituted aryl, substituted heterocycle, or a substituted heteroaryl the substituent can be one to three R b groups, as described above.
- R 16 in a compound of formula (M-Ia) that includes a further substituted group e.g., substituted alkyl, substituted alkoxy, substituted alkylsulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, or substituted alkyloxycarbonyl
- the substituent can be one to three R b groups as described above.
- each R b group can optionally and independently be C (1-6) alkyl, halogen, nitrile, hydroxyl, C (1-6) alkoxy, amino, -OP(O)(OR a ) 2 , and - C (1-6) alkyl-OP(O)(OR a ) 2 , where each R a may be the same or different and is chosen from H, and C (1-6) alkyl.
- This disclosure includes macrocyclic compounds with X 4 being an oxygen atom. Alternatively, X 4 is S. Sometimes, X 4 is CH2.
- macrocyclic compounds where Y 2 and Y 3 are selected from hydrogen, methyl, chloro, fluoro, and nitrile.
- This disclosure also includes macrocyclic compounds where each of R 6 , R 7 , R 11 , Y 2 and Y 3 can be hydrogen or methyl.
- Y 2 and Y 3 are both hydrogen.
- R 6 , and R 11 are both methyl.
- R 7 , Y 2 and Y 3 are each hydrogen.
- R 9 and R 10 can be cyclically linked (-R 9 *R 10 -) to provide a second aryl ring, thus providing a naphthyl group.
- R 8 and R 9 can be cyclically linked (-R 9 *R 10 -) to provide a second aryl ring, thus providing a naphthyl group.
- This disclosure includes compounds where Z 1 is selected from -C(O)OH, - C(O)OCH 2 OP(O)(OH) 2 , -C(O)NHSO 2 -alkyl, and -C(O)NHSO 2 -aryl, or a pharmaceutically acceptable salt thereof.
- This disclosure includes compounds where Z 1 is -C(O)OH.
- This disclosure includes compounds where Z 1 is -C(O)OCH 2 OP(O)(ONa) 2 .
- This disclosure includes compounds were Z 1 is -C(O)NHSO 2 -alkyl, or -C(O)NHSO 2 -aryl.
- This disclosure includes macrocyclic compounds with Z 1 is of the formula -C(O)Z 2 , where Z 2 is selected from -OR 1 and -NHSO 2 R 3 , and where R 1 is H or -(CH 2 ) n OP(O)(OR 2 ) 2 , R 2 is H or C (1-6) alkyl, and R 3 is C (1-6) alkyl, substituted C (1-6) alkyl, aryl, or substituted aryl, where the substituted C (1-6) alkyl and the substituted aryl are substituted with one to three R b groups as described above.
- This disclosure also includes macrocyclic compounds where R 8 is hydrogen.
- the macrocyclic compound of Formula (M-Ia) can be further described by Formula (M-IIa): wherein: Z 2 is selected from -OR 1 , and -NHSO 2 R 3 ; R 1 is selected from H, and -(CH 2 ) n OP(O)(OR 2 ) 2 ; R 2 is selected from H, and C (1-6) alkyl; R 3 is selected from C (1-6) alkyl, substituted C (1-6) alkyl, aryl, and substituted aryl; Y 1 is selected from chloro, fluoro, nitrile, and C 1-6 alkyl; X 2 is selected from O, S, NR 4b , and SO 2 ; X 3 is selected from S and CH2; R 9 -R 10 are each independently selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, halogen, nitrile, and trifluoromethyl; or R 9 and R 10 together with the atoms
- R 3 , and R 8 -R 10 and R 16a in a compound of formula (M-IIa) that include a substituted C (1-6) alkyl, a substituted aryl, or a substituted C (1-6) alkoxy the substituent can be one to three R b groups as described above.
- This disclosure includes macrocyclic compounds with Z 2 is OH.
- This disclosure also includes macrocyclic compounds where R 9 and R 10 are independently selected from H, C (1-6) alkyl, halogen, nitrile, and trifluoromethyl.
- This disclosure also includes macrocyclic compounds were R 9 and R 10 together with the atoms to which they are attached from a 5 or 6 membered aryl ring optionally substituted with one or more R 16a groups, where each R 16a group is independently selected from C (1-6) alkyl, C (1-6) alkoxy, substituted C (1-6) alkoxy, halogen, nitrile and hydroxyl, where the substituted C (1-6) alkoxy is substituted with one to three R b groups as described above.
- R 16a group is independently selected from C (1-6) alkyl, C (1-6) alkoxy, substituted C (1-6) alkoxy, halogen, nitrile and hydroxyl, where the substituted C (1-6) alkoxy is substituted with one to three R b groups as described above.
- Y 1 is selected from halogen, nitrile, and C (1-6) alkyl
- X 2 is selected from O, S, NR 4b , and SO 2
- X 3 is selected from S and CH2
- R 9 -R 10 are each independently selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, halogen, nitrile, and trifluoromethyl; or R 9 and R 10 together with the atoms to which they are attached form a 5 or 6 membered aryl ring optionally substituted with one or more R 16a groups
- each R 16a is independently selected from C (1-6) alkyl, substituted C (1-6) alkyl, C (1-6) alkoxy, substituted C (1-6) alkoxy, halogen, nitrile, and hydroxyl
- X 1 is selected from C (1-6) alkyl, halogen, nitrile, and
- R 5 is selected from C (1-6) alkyl, , and
- R 9 -R 10 or R 16a in a compound of formula (M-IIIa) that include a substituted C (1- 6) alkyl, or a substituted C (1-6) alkoxy the substituent can be one to three R b groups as described above.
- This disclosure includes macrocyclic compounds where R 9 and R 10 together with the atoms through which they are connected form a 5-, or 6-membered carbocyclic, heterocyclic, aryl or heteroaryl ring, optionally substituted with one or more R 16a groups.
- R 9 and R 10 can be cyclically linked (-R 9 *R 10 -) to provide a second aryl ring, thus providing a naphthyl group.
- the macrocyclic compound of Formula (M-Ia) can be further described by Formula (M-Ib): wherein: Z 1 is selected from -C(O)OR 1 , -C(O)N(R 2 )SO 2 (R 3 ), -OR 1 , -C(O)R 1 , -C(O)N(R 2 ) 2 ; R 1 is selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, and - (CH2)nOP(O)(OR 2 ) 2 ; R 2 is selected from H, C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl; R 3 is selected from C (1-6) alkyl, substituted C (1-6) alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl;
- R 1 -R 5 , R 8 , R 12 -R 15 , Y 1 -Y 3 and X 1 in a compound of formula (M-Ib) that include a substituted C (1-6) alkyl, a substituted aryl, substituted heterocycle, or a substituted heteroaryl the substituent can be one to three R b groups as described above.
- This disclosure includes macrocyclic compounds of formula (M-Ib) with X 4 being an oxygen atom. Alternatively, X 4 can be S. Sometimes, X 4 is CH2. Also included, are macrocyclic compounds where Y 2 and Y 3 are selected from hydrogen, methyl, chloro, fluoro, and nitrile.
- This disclosure also includes macrocyclic compounds where each of R 6 -R 8 , R 11 -R 15 , Y 2 and Y 3 can be hydrogen or methyl. Sometimes, Y 2 and Y 3 are both hydrogen. Sometimes, R 6 , and R 11 are both methyl. Sometimes, R 7 , R 8 , R 12 -R 15 , Y 2 and Y 3 are each hydrogen. [0058]
- This disclosure includes compounds of formula (M-Ib), where Z 1 is selected from -C(O)OH, -C(O)OCH2OP(O)(OH) 2 , -C(O)NHSO 2 -alkyl, and -C(O)NHSO 2 -aryl, or a pharmaceutically acceptable salt thereof.
- This disclosure includes compounds where Z 1 is -C(O)OH. This disclosure includes compounds where Z 1 is -C(O)OCH2OP(O)(ONa) 2 . This disclosure includes compounds were Z 1 is -C(O)NHSO 2 -alkyl, or -C(O)NHSO 2 -aryl.
- This disclosure includes naphthyl containing macrocyclic compounds where Z 1 is of the formula -C(O)Z 2 , where Z 2 is selected from -OR 1 and -NHSO 2 R 3 , and where R 1 is H or - (CH2)nOP(O)(OR 2 ) 2 , R 2 is H or C (1-6) alkyl, and R 3 is C (1-6) alkyl, C (1-6) substituted alkyl, aryl, or substituted aryl, where the C (1-6) substituted alkyl and substituted aryl groups are substituted by one to three R b groups as described above.
- the macrocyclic compound of Formula (M-Ib) can be further described by Formula (M-IIb):
- Z 2 is selected from -OR 1 , and -NHSO 2 R 3 ;
- R 1 is selected from H, and -(CH 2 ) n OP(O)(OR 2 ) 2 ;
- R 2 is selected from H, and C (1-6) alkyl;
- R 3 is selected from C (1-6) alkyl, substituted C (1-6) alkyl, aryl, and substituted aryl;
- Y 1 is selected from halogen, nitrile, and C (1-6) alkyl;
- X 2 is selected from O, S, NR 4b , and SO 2 ;
- X 3 is selected from S and CH 2 ;
- X 1 is selected from C (1-6) alkyl, halogen, nitrile, , , , and ;
- R 5 is selected from C (1-6) alkyl,
- R 4a is selected from H, and -P(O)(OR 4 ) 2 ;
- R 4 is selected from H, and
- R 3 in a compound of formula (M-IIb) that include a substituted C (1-6) alkyl, or a substituted aryl the substituent can be one to three R b groups as described above.
- This disclosure includes compounds of formula (M-IIb) wherein Z 2 is OH, such that the compound of formula (M-IIb) is represented by the formula (M-IIIb): , wherein the remaining substituents in formula (M-IIIb) are as defined form formula (M-IIb).
- This disclosure includes compounds of any one of formulae (M-I)-(M-IIIb), wherein Y 1 is selected from chloro, fluoro, methyl and nitrile.
- compounds are includes where Y 1 can be chloro.
- This disclosure includes compounds with X 1 being, halogen (e.g., chloro), C 1-6 alkyl (e.g., methyl), substituted C 1-6 alkyl (e.g., CF3), nitrile, or any of the following structures: and where R 4a is selected from H, and -P(O)(OR 4 ) 2 ; R 4 is selected from H, alkyl, and substituted alkyl, where the substituent can be one to three R b groups as described above; and q is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
- X 1 can be halogen.
- X 1 can be chloro.
- X 1 can be methyl.
- X 1 can be -X 1b , where R a is H or P(O)(OH) 2 .
- X 1 can be -X 1b , where R a is H.
- X 1 can be X 1f .
- X 1 can be X 1g , where R 4a is hydrogen or P(O)(OH) 2 .
- X 1 can be X 1g , where R 4a is hydrogen.
- this disclosure includes compounds with X 1 being methyl, X 1b , X 1f , X 1g wherein R 4a is selected from H, and -P(O)(OH) 2 .
- R 5 being, C 1-6 alkyl (e.g., methyl), substituted C 1- 6 alkyl, where the substituent can be one to three R b groups as described above (e.g., CF 3 ), or any of the following structures: (X ) (X ) (X ) (X ) (X ) , and ( ) ( ) where R 4a is selected from H, and -P(O)(OR 4 ) 2 ; R 4 is selected from H, alkyl, and substituted alkyl; and q is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
- R 5 can be C 1- 6 alkyl.
- R 5 can be methyl.
- R 5 can be X 1a , where R 4a is hydrogen or - P(O)(OH) 2 , and p is 1 to 6.
- R 5 can be X 1b , where R 4a is hydrogen or -P(O)(OH) 2 .
- R 5 can be X 1c , where R 4a is hydrogen or P(O)(OH) 2 .
- R 5 can be X 1d , where R 4a is hydrogen or P(O)(OH) 2 .
- R 5 can be R 5a , where R 4 is methyl.
- R 5 can be R 5b .
- This disclosure includes compounds of any one of formulae (M-I)-(M-IIb), where X 2 is selected from O, S, NR 4 , and SO 2 ; R 4 is selected from H and alkyl (e.g., methyl); and X 3 is selected from S and CH2.
- This disclosure includes compounds of any one of formulae (I)-(V), wherein X 2 is S.
- the disclosure also includes compounds of any one of formulae (I)-(V), wherein X 3 is S.
- This disclosure includes compounds where both X 2 and X 3 are S.
- This disclosure includes compounds where X 2 is O and X 3 is S. This disclosure includes compounds where X 2 is NR 4 and X 3 is S. This disclosure includes compounds where X 2 is SO 2 and X 3 is S. This disclosure includes compounds where X 2 is CH2 and X 3 is S. This disclosure includes compounds where X 2 is O and X 3 is CH2. This disclosure includes compounds where X 2 is S and X 3 is CH2. This disclosure includes compounds where X 2 is NR 4 and X 3 is CH2. This disclosure includes compounds where X 2 is SO 2 and X 3 is S. This disclosure includes compounds where X 2 and X 3 are both CH2. [0068] This disclosure includes compounds of Formula (M-IIIb) as defined by the following compounds M1-M35 of Table 1.
- Table 1 Compounds of Formula (M-IIIb) wherein A is ; and B is .
- formulas and structures may also include salt forms.
- acidic forms of the groups are generally depicted for simplicity, however various salt forms are also meant to be included.
- a salt of the compound could include a monovalent cation salt, such as sodium or potassium salt.
- This disclosure includes any one of the described macrocyclic Mcl-1 inhibitor compounds, stereoisomers thereof (e.g., R a and S a isomers), salts thereof (e.g., pharmaceutically acceptable salts), and/or solvate, hydrate and/or prodrug forms thereof. It will be appreciated that all permutations of stereoisomers, salts, solvates, hydrates, and prodrugs are meant to be included in this disclosure.
- Mcl-1 inhibitor compound of this disclosure having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R- configuration or S-configuration or a mixture thereof.
- each axis may independently be of R a -configuration or S a - configuration or a mixture thereof.
- compound M1 may have the structure of M1-1:
- the compound M1 may have the structure of M1-2: [0074]
- compound M33 may have the structure of M33-1: [0075]
- compound M33 may have the structure of M33-2: [0076]
- compound M34 may have the structure of M34-1: [0077]
- compound M34 may have the structure of M34-2: [0078]
- compound M35 may have the structure of M35-1: [0079]
- compound M35 may have the structure of M35-2:
- Bcl-XL inhibitors [0080] This section provides compounds that constitute a means for inhibiting members of the Bcl- XL family. They are suitable for testing as senolytic agents in novel combinations with Mcl-1 inhibitors described above, according to this invention.
- one class of exemplary Bcl-XL inhibitors includes, the sulfonamides that have the following structure (B-Ia): wherein: X 1 is halide, preferably –Cl; X 2 is –COOH; or –SO 2 CH 3 ; X 3 is –SO 2 CF 3 ; –SO 2 CH 3 ; or –NO 2 ; X 5 is –F or –H; R 1 is –CH(CH 3 ) 2 ; R 2 is either –H or –CH 3 , preferably –CH 3 ; R 3 and R 4 are independently either –H or –CH 3 , preferably both –H; n1 is 1 to 3, preferably 2; and R 6 is selected from –OH, , and ; wherein
- the –COOH group of X2 may be phosphorylated as well as or instead of the hydroxyl group, at the user’s option.
- a “phosphorylated” form of a compound is a compound in which one or more –OH or -COOH groups have been substituted with a phosphate group which is either –OPO3H2 or –CnPO3H2 (where n is 1 to 4), such that the phosphate group may be removed in vivo (for example, by enzymolysis).
- a non- phosphorylated or dephosphorylated form has no such group.
- any compound of the formula (B-IIa) includes separately and together both the acid forms of R 7 as shown, and salt forms thereof, such as when R 7 is –P(O)(ONa) 2 or –(C n H 2n )P(O)(ONa) 2 .
- the aryl sulfonamide Bcl-XL inhibitors include those described in US 8,691,184, the disclosure of which is incorporated by reference in its entirety.
- such exemplary aryl sulfonamide Bcl-XL inhibitors include those in Table 2: Table 2
- Bcl-XL inhibitors include the phospholidines that have the following structure (B-Ib): where: R 4 is selected from hydrogen, alkyl, substituted alkyl, nitro, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, cyano, alkylcarbonyl, substituted alkylcarbonyl, C(O)OH, C(O)NH2, halogen, SO 2 NH2, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino and substituted alkylsulfonylamino, alkanoyl, substituted alkanoyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, al
- Each R b group may be the same or different and optionally chosen from C (1-6) alkyl (optionally substituted with one to three R c groups), hydroxyl, C (1-6) alkoxy (e.g., OCH3, or OCF3), - (CR 4 )mOR 4a , -(CR 4 )mcycloalkyl-(OR 4a )p, -(CR 4 )mheterocycloalkyl-(OR 4a )p, -(CR 4 )maryl-(OR 4a )p, - (CR 4 )mheteroaryl-(OR 4a )p, and -(CR 4 )mN(R a ) 2 , halogen, nitrile, acyl, carboxyl, -OP(O)(OR a ) 2 , and - (CR 4 )mOP(O)(OR a ) 2 , where each R a may be the same or different and is chosen from hydrogen, C
- the substituent can be one to three R b groups selected from C (1-6) alkyl, halogen, nitrile, hydroxyl, C (1-6) alkoxy, amino, acyl, carboxy, -OP(O)(OR a ) 2 , and - C (1-6) alkyl-OP(O)(OR a ) 2 , where each R a may be the same or different and is chosen from H, and C (1-6) alkyl.
- This disclosure includes X 1 being O. Alternatively, X 1 can be S.
- Z 11 can be Z 12 .
- This disclosure includes X 2 being NH or NR 22 .
- R 22 can be alkyl or substituted alkyl.
- R 22 is C 1-6 alkyl, such as methyl.
- This disclosure includes X 2 being Z 12 .
- X 2 can also be S.
- every Z 12 of the ring is CH2.
- one or more Z 12 groups of the ring can be substituted with a R 24 and/or R 25 substituent.
- This disclosure includes compounds of Formula (B-IIb) as defined by the following compounds B-1-B-18 of Table 3.
- X 1 can be O.
- X 1 can be S.
- Table 3 Compounds of Formula (B-IIb)
- R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ; n is 1 or 2; Z 6 is selected from O, CHC(O)R 18 , and CH(CH 2 ) p R 18 wherein p is 0-6 and each R 18 is independently –OR, –N(R) 2 , –OP( ⁇ O)(OH) 2 , and –OP( ⁇ O)(OR) 2 wherein each R is independently H, alkyl or substituted alkyl (e.g., a C 1-4 alkyl such as ethyl
- This disclosure includes compounds of Formula (B-IIIb) as defined by the following compounds B37-B42 of Table 4.
- Table 4 Compounds of Formula (B-IIIb)
- This disclosure includes compounds of Formula (B-Ic) as defined by the following compounds B-19-B-36 of Table 5.
- X 1 can be O.
- X 1 can be S.
- Table 5 Compounds of Formula (B-Ic)
- the compound of Formula (B-Ic) can be further described by Formula (B-IIc): where: Y 2 is selected from–OR 52 , –N(R 52 ) 2 , and –OP( ⁇ O)(OR 52 ) 2 ; R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ; n is 1 or 2; R 14 and R 16 are independently hydrogen or halogen; R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 ,CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ; R 51 is selected from C 1-6 alkyl and substituted C 1-6 alkyl; and R 52 is selected from hydrogen, C 1-6 alkyl and substituted C 1-6 alkyl.
- R 14 in any of Formulae (B-Ib)-(B-IIc) R 14 can be one halogen substituent.
- R 14 can be fluoro.
- This disclosure includes compounds where R 17 is SO 2 R 52 , CO 2 R 52 or COR 52 .
- R 17 can be CONR 51 R 52 , CONR 52 SO 2 R 51 or SO 2 NR 51 R 52 .
- R 51 is C 1-6 alkyl or substituted C 1-6 alkyl and R 52 is hydrogen, C 1-6 alkyl or substituted C 1-6 alkyl.
- R 18 can be hydrogen. Sometimes, R 18 is alkyl. Optionally, R 18 can be substituted alkyl.
- R 19 can be hydrogen.
- R 19 can be alkyl.
- R 19 can be substituted alkyl.
- the substituent can be one to three R b groups, as described above.
- the disclosure includes compounds of Formulae (B-Ib)-(B-IIc) including a stereoisomer of a chiral phosphorus stereocenter.
- the compound of any one of Formulae (B-Ib)-(B-IIc) can have either of the following chirality at phosphorus: .
- compound B-37 may have the structure of B-37-1 or B37-2:
- compound B-39 may have the structure of B-39-1 or B39-2:
- any of the Formula (B-Ib), (B-IIb), or (B-Ic) includes compounds where X 1 is O.
- X 1 is S.
- This disclosure includes compounds of formula (B-Ib), (B-IIb) or (B-Ic) where the 5-, 6- or 7- membered heterocyclic ring connecting the N and P atoms includes a sidechain substituent that derives from an amino acid residue.
- one of R 24 and R 25 of a Z 12 group can be a group corresponding to an amino acid sidechain.
- one of R 24 and R 25 can be a sidechain group of an amino acid residue such as alanine, valine, leucine, isoleucine, glutamine, glutamic acid, aspartic acid, asparagine, serine, threonine, cysteine, methionine, lysine, arginine, ornithine, phenylalanine, tyrosine, tryptophan or histidine, or a substituted version thereof.
- the heterocyclic ring includes only one Z 12 group that includes an amino acid derived sidechain, where the remaining Z 12 groups R 24 and R 25 are each hydrogen.
- Z 12 can include a chiral center having a chirality corresponding to an L-amino acid residue.
- Z 12 can have a chirality corresponding to a D-amino acid residue.
- such formulas and structures may also include salt forms where the structure provides for an acidic or basic group.
- the core phospholidine linking moiety of the compounds of this disclosure can be neutral.
- the compound can include a charged moiety (e.g., a basic amino group) at other location(s) of the compound. Where applicable, neutral forms of the groups are generally depicted in the structures for simplicity, however various salt forms are also meant to be included.
- a salt of the compound could include a monovalent cation salt, such as sodium or potassium salt.
- a monovalent cation salt such as sodium or potassium salt.
- Other tautomeric arrangements of the groups depicted in these formulas and structures are possible, and are meant to be included in this disclosure.
- Evaluating compounds for senolytic activity [00108] Bcl-XL inhibitors and Mcl-1 inhibitors can be evaluated on the molecular level for their ability to perform in a way that indicates they are suitable senolytic combinations for use according to this invention.
- candidate Bcl-XL inhibitor or Mcl-1 inhibitor compounds of the invention can be tested for their ability to inhibit binding between one or more Bcl-XL and Mcl-1 proteins and their respective cognate ligand.
- Example 5 provides an immunocapture and co-immunoprecipitation target engagement assay that can simultaneously detect both Bcl-XL and Mcl-1 interactions with BIM in the presence of candidate Bcl-XL and/or Mcl-1 inhibitors.
- Candidate compounds can also be evaluated for an ability to kill senescent cells selectively.
- Cultured cells are contacted with the compound, and the degree of cytotoxicity or inhibition of the cells is determined.
- the ability of the compound to kill or inhibit senescent cells can be compared with the effect of the compound on normal cells that are freely dividing at low density, and normal cells that are in a quiescent state at high density.
- Examples 1-4 provide illustrations of selective senescent cell killing using various cell lines that are induced by irradiation to senesce: a primary human small airway epithelial cell (SAEC), or the primary human bronchial epithelial cells (HBEC), or the human fibroblast IMR90 cell line, or the human endothelial HUVEC cell line.
- SAEC primary human small airway epithelial cell
- HBEC primary human bronchial epithelial cells
- IMR90 cell line or the human endothelial HUVEC cell line.
- Candidate senolytic combinations that are effective in selectively killing senescent cells in vitro can be further screened in animal models for particular diseases.
- Examples 9-15 in the Experimental Section provide illustrations for pulmonary disease, osteoarthritis, glaucoma disease, diabetes-induced retinopathy, atherosclerosis, and other fibrotic diseases respectively. Determining senolytic synergy between Bcl-XL inhibitor and Mcl-1 inhibitor combinations [00112] Many of the effective combinations of Bcl-XL and Mcl-1 inhibitors are attributable at least in part to functional synergy between the two compounds.
- the proteins Bcl-XL, and Mcl-1 are all part of a mitochondrial pathway that regulate caspases 3, 6, and 7, leading to apoptosis.
- Synergy between Bcl-XL inhibitors and Mcl-1 inhibitors may be direct or indirect, leading to enhanced inhibition, decreased regulation of caspase activity, and consequently an increase in apoptosis, leading to elimination of the senescent cell.
- the combination response can be compared against an expected combination response, under the assumption of non-interaction calculated using a reference model (Tang J. et al.
- Commonly-utilized reference models can include, for example, the highest single agent (HSA) model, where the synergy score quantifies the excess over the highest single drug response (Berenbaum M.C. (1989) What is synergy. Pharmacol. Rev., 41, 93–141); the Loewe additivity model, where the synergy score quantifies the excess over the expected response if the two drugs are the same compound (Loewe S. (1953) The problem of synergism and antagonism of combined drugs.
- HSA highest single agent
- SynergyFinder a web application for analyzing drug combination dose–response matrix data. Bioinformatics. Aug 1; 33(15): 2413–2415. The algorithm is publicly available from the Netherlands Translational Research Center, and can be accessed via the Internet.
- Effective combinations of senolytic agents such as Bcl-XL inhibitors and Mcl-1 inhibitors according to this invention may have a ⁇ value, or synergy coefficient that is greater than 5, 10, 15, 20, 30, 50, 80, or 150. Expressed in ranges, the synergy between such compounds may have ⁇ values in the range of 1-500, 10-100, or 20-100.
- Preparation and formulation of pharmaceutical agents for use according to this invention can incorporate standard technology, as described, for example, in the current edition of Remington: The Science and Practice of Pharmacy.
- the formulation will typically be optimized for administration to the target tissue, for example, by local administration, in a manner that enhances access of the active agent to the target senolytic cells and providing the optimal duration of effect, while minimizing side effects or exposure to tissues that are not involved in the condition being treated.
- Pharmaceutical preparations for use in treating senescence-related conditions and other diseases can be prepared by mixing the candidate Bcl-XL or Mcl-1 inhibitors with a pharmaceutically acceptable base or carrier and as needed one or more pharmaceutically acceptable excipients.
- excipients and additives that can be used include surfactants (for example, polyoxyethylene and block copolymers); buffers and pH adjusting agents (for example, hydrochloric acid, sodium hydroxide, phosphate, citrate, and sodium cyanide); tonicity agents (for example, sodium bisulfite, sodium sulfite, glycerin, and propylene glycol); and chelating agents (for example, ascorbic acid, sodium edetate, and citric acid).
- surfactants for example, polyoxyethylene and block copolymers
- buffers and pH adjusting agents for example, hydrochloric acid, sodium hydroxide, phosphate, citrate, and sodium cyanide
- tonicity agents for example, sodium bisulfite, sodium sulfite, glycerin, and propylene glycol
- chelating agents for example, ascorbic acid, sodium edetate, and citric acid.
- the senolytic combinations of the invention may be formulated, for example, for intravitreal or intracameral administration.
- the senolytic combinations of the invention may be formulated, for example, as an aerosol for intratracheal administration.
- the senolytic combinations of the invention may be formulated, for example, for systemic administration, which can take place via enteral administration (absorption of the drug through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation).
- kits that enclose unit doses of one or more of the agents or compositions described in this disclosure.
- kits typically comprise a pharmaceutical preparation in one or more containers.
- the preparations may be provided as one or more unit doses (either combined or separate).
- the kit may contain a device such as a syringe for administration of the senolytic agent or composition in or around the target tissue of a subject in need thereof.
- the product may also contain or be accompanied by an informational package insert describing the use and attendant benefits of the senolytic drugs in treating the senescence-associated disease, and optionally a device for delivery of the senolytic drugs.
- Senescent cells accumulate with age, which is why diseases and/or disorders mediated by senescent cells occur more frequently in older adults.
- different types of stress on tissues may promote the emergence of senescent cells and the phenotype they express.
- Cell stressors include oxidative stress, metabolic stress, DNA damage (for example, as a result of environmental ultraviolet light exposure or genetic disorder), oncogene activation, and telomere shortening (resulting, for example, from hyperproliferation). Tissues that are subject to such stressors may have a higher prevalence of senescent cells, which in turn may lead to presentation of certain conditions at an earlier age, or in a more severe form.
- Such conditions can be characterized by an overabundance of senescent cells or that senescent cells are secreting SASPs in or around the site of the disease, in comparison with the number of such cells or the level of such expression in unaffected cells and/or tissues.
- senescence-associated diseases include the treatment of osteoarthritis, eye disease, lung disease, atherosclerosis, and liver disease, as illustrated in the following sections.
- Treatment of osteoarthritis [00124]
- the senolytic combinations of the invention can be developed for treating osteoarthritis.
- the senolytic combinations of the invention can be developed for selectively eliminating senescent cells in or around a joint of a subject in need thereof, including but not limited to a joint affected by osteoarthritis.
- Osteoarthritis degenerative joint disease is characterized by fibrillation of the cartilage at sites of high mechanical stress, bone sclerosis, and thickening of the synovium and the joint capsule. Fibrillation is a local surface disorganization involving splitting of the superficial layers of the cartilage. The early splitting is tangential with the cartilage surface, following the axes of the predominant collagen bundles. Collagen within the cartilage becomes disorganized, and proteoglycans are lost from the cartilage surface. In the absence of protective and lubricating effects of proteoglycans in a joint, collagen fibers become susceptible to degradation, and mechanical destruction ensues.
- Predisposing risk factors for developing osteoarthritis include increasing age, obesity, previous joint injury, overuse of the joint, weak thigh muscles, and genetics. Symptoms of osteoarthritis include sore or stiff joints, particularly the hips, knees, and lower back, after inactivity or overuse; stiffness after resting that goes away after movement; and pain that is worse after activity or toward the end of the day.
- the senolytic combinations of the invention can be used to reduce pain and inflammation in the affected joint.
- the senolytic combinations of the invention may be administered directly to an osteoarthritic joint, for example, intra-articularly.
- Ophthalmic conditions treatable with the senolytic combinations of the invention include ischemic or vascular conditions, such as diabetic retinopathy, glaucomatous retinopathy, ischemic arteritic optic neuropathies, and vascular diseases characterized by arterial and venous occlusion, retinopathy of prematurity and sickle cell retinopathy.
- Retinoblastoma is another ophthalmic condition contemplated.
- ophthalmic conditions treatable with the senolytic combinations of the invention include degenerative conditions, such as dermatochalasis, ptosis, keratitis sicca, Fuch’s corneal dystrophy, presbyopia, cataract, wet age related macular degeneration (wet AMD), dry age related macular degeneration (dry AMD); degenerative vitreous disorders, including vitreomacular traction (VMT) syndrome, macular hole, epiretinal membrane (ERM), retinal tears, retinal detachment, and proliferative vitreoretinopathy (PVR).
- degenerative conditions such as dermatochalasis, ptosis, keratitis sicca, Fuch’s corneal dystrophy, presbyopia, cataract, wet age related macular degeneration (wet AMD), dry age related macular degeneration (dry AMD); degenerative vitreous disorders, including vitreomacular traction (VMT) syndrome, macular hole, epiretinal membrane (ERM), retinal
- ophthalmic conditions treatable with the senolytic combinations of the invention include genetic conditions, such as retinitis pigmentosa, Stargardt disease, Best disease and Leber’s hereditary optic neuropathy (LHON).
- Ophthalmic conditions treatable with the senolytic combinations of the invention include conditions caused by a bacterial, fungal, or virus infection. These include conditions caused or provoked by an etiologic agent such as herpes zoster varicella (HZV), herpes simplex, cytomegalovirus (CMV), and human immunodeficiency virus (HIV).
- HZV herpes zoster varicella
- CMV cytomegalovirus
- HAV human immunodeficiency virus
- Still further ophthalmic conditions treatable with the senolytic combinations of the invention include inflammatory conditions, such as punctate choroiditis (PIC), multifocal choroiditis (MIC) and serpiginous choroidopathy.
- Ophthalmic conditions treatable with the senolytic combinations of the invention also include iatrogenic conditions, such as a post-vitrectomy cataract and radiation retinopathy.
- Treatment of pulmonary diseases [00132]
- the senolytic combinations of the invention can be developed for treating pulmonary disease in accordance with this invention.
- the senolytic combinations of the invention can be developed for selectively eliminating senescent cells in or around a lung of a subject in need thereof.
- Pulmonary conditions that can be treated according to this invention include idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, including primary ciliary dyskinesia (PCD), and emphysema. Pulmonary diseases such as the aforementioned can also be exacerbated by tobacco smoke, occupational exposure to dust, smoke, or fumes, infection, or pollutants that contribute to inflammation. [00133] The methods of this invention for treating or reducing the likelihood of a pulmonary condition can also be used for treating a subject who is aging and has loss of pulmonary function, or degeneration of pulmonary tissue.
- the respiratory system can undergo various anatomical, physiological and immunological changes with age.
- the structural changes include chest wall and thoracic spine deformities that can impair the total respiratory system compliance resulting in increased effort to breathe.
- the respiratory system undergoes structural, physiological, and immunological changes with age.
- An increased proportion of neutrophils and lower percentage of macrophages can be found in bronchoalveolar lavage (BAL) of older adults compared with younger adults.
- BAL bronchoalveolar lavage
- Persistent low grade inflammation in the lower respiratory tract can cause proteolytic and oxidant-mediated injury to the lung matrix resulting in loss of alveolar unit and impaired gas exchange across the alveolar membrane seen with aging.
- Sustained inflammation of the lower respiratory tract can predispose older adults to increased susceptibility to toxic environmental exposure and accelerated lung function decline.
- Oxidative stress exacerbates inflammation during aging. Alterations in redox balance and increased oxidative stress during aging precipitate the expression of cytokines, chemokines, and adhesion molecules, and enzymes. Constitutive activation and recruitment of macrophages, T cells, and mast cells foster release of proteases leading to extracellular matrix degradation, cell death, remodeling, and other events that can cause tissue and organ damage during chronic inflammation. [00134] Effects of treatments of the invention can be determined using techniques that evaluate mechanical functioning of the lung, for example, techniques that measure lung capacitance, elastance, and airway hypersensitivity can be performed.
- any one of numerous measurements can be obtained, for example, expiratory reserve volume (ERV), forced vital capacity (FVC), forced expiratory volume (FEV) (e.g., FEV in one second, FEV1), FEV1/FEV ratio, forced expiratory flow 25% to 75%, and maximum voluntary ventilation (MVV), peak expiratory flow (PEF), slow vital capacity (SVC).
- Total lung volumes include total lung capacity (TLC), vital capacity (VC), residual volume (RV), and functional residual capacity (FRC).
- Gas exchange across alveolar capillary membrane can be measured using diffusion capacity for carbon monoxide (DLCO).
- Peripheral capillary oxygen saturation (SpO 2 ) can also be measured; normal oxygen levels are typically between 95% and 100%.
- An SpO 2 level below 90% suggests the subject has hypoxemia. Values below 80% are considered critical and require intervention to maintain brain and cardiac function and avoid cardiac or respiratory arrest.
- Treatment of hepatic diseases [00136] Mortality rates for chronic liver disease are rising, and pose a serious burden on health care systems worldwide. Chronic liver disease results in liver inflammation. This in turn leads to loss of functional hepatocytes, fibrosis, and ultimately cirrhosis and increased risk for liver cancer. In late-stage liver disease, decompensation of the liver leads to mortality rates of up to 85% within 5 years, unless the patent is fortunate above to have a liver transplant.
- Liver disease can arise from a diversity of causes including infection, genetic disorders, dietary lifestyle choices and substance abuse. These include infection with Hepatitis B or C viruses (viral hepatitis), excessive alcohol intake (alcoholic hepatitis), autoimmune-associated disease (primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis), and genetic disorders such as ⁇ 1 antitrypsin deficiency and hemochromatosis (arising from specific mutations in susceptibility genes A1AT and HFE, respectively). Some diseases arise from a combination of metabolic disease, diet and genetic predisposition. These include non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- liver diseases also include acute-on chronic liver failure (ACLF), and hepatic encephalopathy (HE). Any of these conditions can lead to severe chronic liver disease, and ultimately hepatic failure or liver transplant.
- ACLF acute-on chronic liver failure
- HE hepatic encephalopathy
- This invention provides a new approach to treating liver disease by eliminating senescent cells that reside in or around the site of the disease pathophysiology. Senescent cells having particular features have been identified as suitable targets for pharmacological intervention. Removal of senescent cells from affected sites using small molecule agents that specifically target senescent cells can help ameliorate signs and symptoms of liver disease, and prevent progression to more severe stages of the disease.
- screening candidate senolytic combinations of the invention for selective elimination of p16-expressing hepatocytes or cholangiocytes can be performed as follows. In chronic liver diseases, both hepatocytes and cholangiocytes have been implicated as contributing to populations of p16-expressing senescent cells.
- cryopreserved human hepatocytes obtained from SigmaAldrich ®
- primary cryopreserved human cholangiocytes obtained from Celprogen ®
- cells are challenged with a small molecule compound that induces senescence, or with radiation.
- a dose-response time course of senescence induction can be used to assess the kinetics of expression of p21 and p16 during this process.
- senolytic agents for selective elimination of senescent hepatocytes or cholangiocytes
- various doses of senolytic compounds are compared with vehicle treatments to assess the number of p16 and p21 expressing cells that survive after a defined period of treatment (typically 1 to 5 days).
- Assessment of total cell viability in this assay is performed using Cell-Titer GlowTM assay (Promega ® ) to control for compounds that induce non-specific cell death.
- Vehicle and senolytic compound treatment groups are compared by quantitation of cells positive for p16, p21, both or neither as quantified using high content microscopic immunocytochemical methods with antibodies against p16, p21 (Dako ® ) and DAPI nuclear stain to determine selectivity indexes for p16, p21, and p16/p21.
- the STAM TM mouse model of NASH recapitulates the histological progression of NASH observed in human patients and includes similar effects on liver function and development of hepatocellular carcinoma (Saito, T et al., Intern Med.2007;46(2):101-3, and Saito, K et al., Physiol Res.2017 Nov 24;66(5):791-799).
- animals are injected with streptozotocin (STZ) to ablate pancreatic beta-cells and induce metabolic disease in the form of insufficient insulin formation.
- HFD high fat diet
- NAFLD sever metabolic disease and NAFLD, which progresses in a predictable time course to NASH and ultimately to hepatocellular carcinoma (HCC) by 20 weeks.
- HFD high fat diet
- NAFLD sever metabolic disease and NAFLD
- HCC hepatocellular carcinoma
- treatment of the mice with a senolytic agent can begin 5 to 12 weeks after HFD is initiated.
- the candidate senolytic combinations of the invention are dosed systemically, enterally or parenterally as needed.
- a positive end-point may be shown by reduction of p16-positive cells in liver parenchyma any time between 6 and 20 weeks after initiation.
- a positive end point may also be shown by reduction of fibrosis, as determined by Sirius red or trichome histology at 20 weeks. Reduction of either of these markers may correlate with a reduced likelihood of HCC development in the model, which can be assessed by quantitation of tumor burden and nodule formation at 20 weeks.
- the senolytic compounds, conjugates, and formulations of this invention can be administered for the treatment or prevention of liver disease at any stage. It is often desirable to assess patients that will progress to an acute liver insult such as acute hepatitis, NAFLD, or NASH, to cirrhosis and ultimately to liver failure. Assessing liver function can be done according to standard tests for liver function, including serum markers and characteristic liver histopathology. Candidate patients can be graded for disease progression prior to end stage disease as described by Eddowes et al., Aliment Pharmacol Ther. 2018 Mar;47(5):631-644.
- Efficacy of senolytic treatment can be measured by changes in circulating liver enzyme levels (aspartate transaminase (AST) and alanine transaminase (ALT)), the five-year risk score for requiring a liver transplant, development of HCC, and progression-free survival.
- Treatment of atherosclerosis [00145] Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries; the plaques contain lipids, inflammatory cells, smooth muscle cells, and connective tissue.
- Atherosclerosis can affect large and medium-sized arteries, including the coronary, carotid, and cerebral arteries, the aorta and its branches, and major arteries of the extremities.
- Atherosclerosis is a syndrome affecting arterial blood vessels due in significant part to a chronic inflammatory response of white blood cells in the walls of arteries. This is promoted by low-density lipoproteins (LDL, plasma proteins that carry cholesterol and triglycerides) in the absence of adequate removal of fats and cholesterol from macrophages by functional high-density lipoproteins (HDL).
- LDL low-density lipoproteins
- HDL functional high-density lipoproteins
- the earliest visible lesion of atherosclerosis is the “fatty streak,” which is an accumulation of lipid-laden foam cells in the intimal layer of the artery.
- Atherosclerotic plaque which is an evolution of the fatty streak and has three major components: lipids (e.g., cholesterol and triglycerides); inflammatory cells and smooth muscle cells; and a connective tissue matrix that may contain thrombi in various stages of organization and calcium deposits.
- lipids e.g., cholesterol and triglycerides
- inflammatory cells and smooth muscle cells e.g., IL-12 and IL-12
- a connective tissue matrix that may contain thrombi in various stages of organization and calcium deposits.
- Lipid-rich atheromas are at increased risk for plaque rupture and thrombosis. Reports have found that of all plaque components, the lipid core exhibits the highest thrombogenic activity. Within major arteries in advanced disease, the wall stiffening may also eventually increase pulse pressure. [00148] A vulnerable plaque that may lead to a thrombotic event (stroke or myocardial infarction (MI), commonly known as a heart attack) and is sometimes described as a large, soft lipid pool covered by a thin fibrous cap.
- MI myocardial infarction
- An advanced characteristic feature of advance atherosclerotic plaque is irregular thickening of the arterial intima by inflammatory cells, extracellular lipid (atheroma) and fibrous tissue (sclerosis.
- Fibrous cap formation is believed to occur from the migration and proliferation of vascular smooth muscle cells and from matrix deposition.
- a thin fibrous cap contributes instability of the plaque and to increased risk for rupture.
- the methods and senolytic combinations according to this invention may have any one or more of the following effects: inhibit formation, increase stability, increase fibrous cap thickness, decrease lipid concentration of atherosclerotic plaques, inhibit calcium deposition in blood vessels, preventing or inhibiting progression of angina, and thus decreasing the risk of an infarction. Definitions [00150]
- a “senescent cell” is generally thought to be derived from a cell type that typically replicates, but as a result of aging or other event that causes a change in cell state, can no longer replicate.
- senescent cells can be identified as, for example, expressing p16, or at least one marker selected from p16, senescence-associated ⁇ -galactosidase, and lipofuscin; sometimes two or more of these markers, and other markers of SASP such as, but not limited to, interleukin 6, and inflammatory, angiogenic and extracellular matrix modifying proteins.
- a “senescence-associated”, “senescence-related” or “age-related” disease, disorder, or condition as referred to in this disclosure is a physiological condition that is caused or mediated in part by senescent cells, which may be induced by multiple etiologic factors including age, DNA damage, oxidative stress, genetic defects, etc. Lists of senescence associated diseases can potentially be treated or managed using the methods and compounds taught in this disclosure.
- a compound, composition or agent is typically referred to as “senolytic” if it eliminates senescent cells and/or senescent cells that secrete SASPs rather than replicative cells of the same tissue type (non-senescent cells), or quiescent cells lacking SASP markers.
- the methods and senolytic combinations of the invention may effectively be used if it decreases the release of pathological soluble factors or mediators as part of the senescence associated secretory phenotype (SASP) that play a role in the initial presentation or ongoing pathology of a condition, or inhibit its resolution.
- SASP senescence associated secretory phenotype
- the term “senolytic” is exemplary, with the understanding that compounds that work primarily by inhibiting rather than eliminating senescent cells (senescent cell inhibitors) can be used in a similar fashion with ensuing benefits.
- disease disorders
- condition is used interchangeable to refer to any condition of a human or animal body that has signs, symptoms, and/or phenotypical features that are in some respects undesirable to the subject, for which the subject desires is deemed to be worthy of treatment according to this invention.
- Successful “treatment” of a senescence-associated disease may have any effect that is beneficial to the subject being treated. This includes decreasing the severity, duration, or progression of a senescence-associated disease, or of any adverse signs or symptoms resulting therefrom.
- senolytic agents can also be used to prevent or inhibit presentation of a senescence- associated disease for which a subject is susceptible, for example, because of an inherited susceptibility or because of medical history.
- “Enhancement of senolytic activity” means the ability for the combination therapies of the invention to demonstrate a synergistic senolytic activity on senescent cells, which is more than an additive senolytic activity of each individual senolytic compound by itself. This can be calculated by using, for example, the Zero interaction potency (ZIP) model, described herein and in Example 7.
- ZIP Zero interaction potency
- a “phosphorylated” form of a compound is a compound in which one or more –OH or -COOH groups have been substituted with a phosphate group which is either –OPO3H2 or –CnPO3H2 (where n is 1 to 4). This includes phosphorylated forms that act as prodrugs by including a phosphate group that may be removed in vivo (for example, by enzymolysis). A non-phosphorylated or dephosphorylated form has no such group.
- Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. The transformation can be an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
- each of the compound structures referred to in the invention include conjugate acids and bases having the same structure, crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and prodrugs. This includes, for example, polymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), and phosphorylated and unphosphorylated forms of the compounds.
- alkenyl refers to a monovalent linear or branched chain group of one to twelve carbon atoms, and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms, derived from a straight or branched chain hydrocarbon (hydrocarbyl) containing at least one carbon-carbon double bond.
- alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
- alkoxyalkyl refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
- alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
- alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
- alkoxycarbonylalkyl refers to an alkoxycarbonyl group attached to the parent molecular moiety through an alkyl group.
- alkyl refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 12 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms.
- This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3) 2 CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
- linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3) 2 CHCH2-), sec-
- alkylaminosulfonyl refers to an alkylamino group attached to the parent molecular moiety through a sulfonyl group.
- alkylsulfanyl refers to an alkyl group attached to the parent molecular moiety through a sulfur atom (-S-).
- alkylsulfinyl refers to an alkyl group attached to the parent molecular moiety through a sulfinyl group (-SO-).
- alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group (-SO 2 -).
- alkylsulfonylalkyl refers to an alkylsulfonyl group attached to the parent molecular moiety through an alkyl group.
- alkylsulfonylalkyl refers to an alkylsulfonyl group attached to the parent molecular moiety through an amino group (-NR a -) wherein R a is hydrogen, alkanoyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, alkylaminoalkyl, alkylaminocarbonylalkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, haloalkanoyl, haloalkyl, (heterocycle)alkyl, heterocyclecarbonyl, hydroxyalkyl, a nitrogen protecting group, —C(NH)NH 2 , or —C(O)NR c R d , where R c and R d are hydrogen, alkyl, aryl, heteroaryl, carb
- alkynyl refers to a straight or branched chain hydrocarbyl group of one to twelve carbon atoms, and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms, containing at least one carbon-carbon triple bond.
- amino refers to —NR a R b , wherein R a and R b are hydrogen, alkanoyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, alkylaminoalkyl, alkylaminocarbonylalkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, haloalkanoyl, haloalkyl, (heterocycle)alkyl, heterocyclecarbonyl, hydroxyalkyl, a nitrogen protecting group, —C(NH)NH 2 , or —C(O)NR c R d , where R c and R d are hydrogen, alkyl, aryl, heteroaryl, carbocycle or heterocycle; wherein the aryl; the aryl part of the arylalkyl;
- aminosulfonyl refers to an amino group attached to the parent molecular moiety through a sulfonyl group.
- Aryl or “Ar” refer to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings, e.g., a bicyclic fused ring system or a tricyclic fused ring system (examples of such aromatic ring systems include naphthyl, anthryl and indanyl), which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring.
- Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, or another phenyl group.
- Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, or another phenyl group.
- such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thi
- arylalkoxy refers an aryl group attached to the parent molecular moiety through an alkoxy group.
- arylalkyl refers an aryl group attached to the parent molecular moiety through an alkyl group.
- arylcycloalkenylalkyl refers a bicyclic aryl-cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
- arylheteroarylalkyl refers a bicyclic aryl-heteroaryl group attached to the parent molecular moiety through an alkyl group.
- aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
- aryloxyalkoxy refers an aryloxy group attached to the parent molecular moiety through an alkoxy group.
- aryloxyalkyl refers to an aryloxy group attached to the parent molecular moiety through an alkyl group.
- arylsulfanyl refers to an aryl group attached to the parent molecular moiety through a sulfur atom (-S-).
- arylsulfanylalkoxy refers to an arylsulfanyl group attached to the parent molecular moiety through an alkoxy group.
- arylsulfanylalkyl refers to an arylsulfanyl group attached to the parent molecular moiety through an alkyl group.
- arylsulfinyl refers to an aryl group attached to the parent molecular moiety through a sulfinyl group (-SO-).
- arylsulfinylalkyl refers to an arylsulfinyl group attached to the parent molecular moiety through an alkyl group.
- arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group (-SO 2 -).
- arylsulfonylalkyl refers to an arylsulfonyl group attached to the parent molecular moiety through an alkyl group.
- biasryl unless indicated otherwise, refers to a group including two aryl rings linked via a single covalent bond.
- biasrylalkyl refers to a biaryl group attached to the parent molecular moiety through an alkyl group.
- C1-nalkyl linker where n is an integer of 1 to 100, e.g., n is 2, 3, 4, 5, 6, or more, refers to a divalent alkyl linker that connects two groups and has a backbone of “n” atoms in length. The divalent alkyl linker is optionally substituted.
- the terms “carbocycle” and “carbocyclic” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused, bridged and spiro ring systems, and having from 3 to 20 ring carbon atoms.
- one or more of the rings can be cycloalkyl or aryl, provided that the point of attachment is through the non-aromatic ring.
- carbonyloxy refers to an alkanoyl group attached to the parent molecular moiety through an oxygen atom.
- carboxy refers to an alkanoyl group attached to the parent molecular moiety through an oxygen atom.
- carboxyl refers to —CO 2 H or salts thereof.
- carboxyalkyl refers to a carboxy group attached to the parent molecular moiety through an alkyl group.
- Cyano or “nitrile” refers to the group –CN.
- cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
- cycloalkenylalkyl refers to a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
- cycloalkyl refers to a saturated carbocyclic ring system having three to twelve carbon atoms and one to three rings including fused, bridged, and spiro ring systems.
- cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, bicyclo(3.1.1)heptyl, adamantyl, and the like.
- the cycloalkyl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy, aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl and hydroxy, where the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl and hydroxy.
- cycloalkylalkoxy refers to a cycloalkyl group attached to the parent molecular moiety through an alkoxy group.
- cycloalkylalkyl refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
- cycloalkylcarbonyl refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group (-CO-).
- cycloalkyloxy refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.
- dialkylamino refers to —N(R) 2 , wherein each R is alkyl.
- haloalkoxy refers to an alkoxy group substituted by one, two, three, or four halogen atoms.
- haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
- Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring.
- heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic , provided that the point of attachment is through an atom of an aromatic ring.
- a single ring such as, pyridinyl, imidazolyl or furyl
- multiple condensed rings in a ring system for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl
- the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
- N ⁇ O N-oxide
- sulfinyl N-oxide
- sulfonyl moieties N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
- This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
- heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
- heteroarylalkyl refers a heteroaryl group attached to the parent molecular moiety through an alkyl group.
- heteroarylarylalkyl refers a bicyclic heteroaryl-aryl group attached to the parent molecular moiety through an alkyl group.
- arylcycloalkenylalkyl refers a bicyclic heteroaryl-cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
- heteroaryloxy refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom.
- heteroaryloxyalkyl refers a heteroaryloxy group attached to the parent molecular moiety through an alkyl group.
- heteroarylsulfanylalkyl refers to a heteroarylsulfanyl group attached to the parent molecular moiety through an alkyl group.
- heteroarylsulfinylalkyl refers to a heteroarylsulfinyl group attached to the parent molecular moiety through an alkyl group.
- heteroarylsulfonylalkyl refers to a heteroarylsulfonyl group attached to the parent molecular moiety through an alkyl group.
- heterocycle-sulfanylalkyl refers to a heterocycle group attached to the parent molecular moiety through a sulfonyl (-S-) and an alkyl group.
- Heterocycle “heterocyclic” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused, bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring heteroatoms are selected from nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
- the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or –SO 2 - moieties.
- the heterocycle When the heterocycle is saturated it may be referred to as a “heterocycloalkyl”.
- hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
- linker or “linkage” refers to a linking moiety that connects at least two groups and has a backbone of 100 atoms or less in length between the at least two groups.
- a linker may be a covalent bond that connects two groups or a group having a backbone of between 1 and 100 atoms in length, for example a backbone of 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20 carbon atoms in length, where the linker may be linear, branched, cyclic or a single atom.
- a linker that is branched can connect three groups (i.e., trivalent).
- one, two, three, four or five or more carbon atoms of a linker backbone may be optionally substituted with a sulfur, nitrogen or oxygen heteroatom.
- the bonds between backbone atoms may be saturated or unsaturated, where usually not more than one, two, or three unsaturated bonds will be present in a linker backbone.
- the linker may include one or more substituent groups, for example an alkyl, aryl, heteroaryl or alkenyl group.
- a linker may include, without limitations, ethylene glycol or poly(ethylene glycol) units, ethers, thioethers, tertiary amines, alkyls, which may be straight or branched, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
- the linker backbone may include a cyclic group, for example, an aryl, a heteroaryl, a heterocycle or a cycloalkyl group, where 2 or more atoms, e.g., 2, 3 or 4 atoms, of the cyclic group are included in the backbone.
- a linker may be cleavable or non-cleavable.
- the term “monoalkylamino” refers to —NHR, where R is alkyl.
- substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
- Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 )4; or an alkaline earth ion, such as [Ca 2+ ]0.5, [Mg 2+ ]0.5, or [Ba 2+ ]0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions).
- an alkali ion such as K + , Na + , Li +
- an ammonium ion such as + N(R 60 )4
- an alkaline earth ion such as
- -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl- piperazin-1-yl and N-morpholinyl.
- substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 60 , halo, -O-M + , -OR 70 , -SR 70 , -S – M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO 2 , -N3, -SO 2 R 70 , -SO3 – M + , -SO3R 70 , -OSO 2 R 70 , -OSO3 – M + , -OSO
- substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O-M + , -OR 70 , -SR 70 , -S-M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O-M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 , -OS(O) 2 O-M + , -O S(O) 2 OR 70 , -P(O)(O-) 2 (M + ) 2 , -P(O)(OR 70 )O-M + , -P(O)(OR 70 )(OR 70 ), -C(O
- a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
- substituents with further substituents to themselves e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.
- the maximum number of such substitutions is three.
- substituted alkoxy refers to a substituted alkyl group attached to the parent molecular moiety through an oxygen atom.
- substituted alkyl refers to an alkyl group where one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as O-, N-, S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioal
- Example 1 Inducing Senescence in Primary Human Cells
- SAEC Primary human small airway epithelial cells
- HBEC human bronchial epithelial cells
- SAEC Primary human small airway epithelial cells
- HBEC human bronchial epithelial cells
- Cells were maintained and propagated at ⁇ 75% confluency in Airway Epithelial Cell Growth Medium or Small Airway Epithelial Cell Growth Medium (Promocell ® ; Heidelberg, Germany) at 20% O2, 5% CO2, and ⁇ 95% humidity.
- x-ray irradiation was employed.
- SAEC or HBEC cells were covered with TrypLE trypsin-containing reagent (Thermofisher Scientific ® , Waltham, Massachusetts) and incubated for 8 min until the cells rounded up and began to detach from the plate. Cells were dispersed, counted, and prepared in medium at a concentration of 94,400 cells per mL. This cell suspension was plated in 384-well plates at a volume of 25 ⁇ L per well (2360 cells/well). Within 24-hours after cell plating, the 384-well plates were irradiated at 12 Gy to generate senescent cells (SnC).
- SnC senescent cells
- control 384-well plates were processed in parallel that were not irradiated and served as controls and represent normal, non-senescent cells (NsC).
- NsC normal, non-senescent cells
- the medium in each well was aspirated and replaced with 25 ⁇ L fresh medium.
- senescence of cells was determined through senescence ⁇ -galactosidase staining (Biovision ® , Cat. K320-250).
- qPCR was performed using Cells-to-CT to measure relative gene expression by real-time RT-PCR and TaqMan detection chemistry (ThermoFisher Scientific ® , Cat.
- FIG.1 panels A-D demonstrate the ability to induce senescence in primary human epithelial cells by irradiation, where FIG.
- Example 2 Measuring senolytic activity of candidate senolytic agents in senescent fibroblasts
- Human fibroblast IMR90 cells can be obtained from the American Type Culture Collection (ATCC ® ) with the designation CCL-186. The cells are maintained at ⁇ 75% confluency in DMEM containing FBS and Pen/Strep in an atmosphere of 3% O 2 , 10% CO 2 , and ⁇ 95% humidity.
- the cells are divided into groups: irradiated cells (cultured for 14 days after irradiation prior to use) and quiescent cells (cultured at high density for four days prior to use).
- the irradiated cells can be prepared as follows. IMR90 cells are washed, placed in T175 flasks at a density of 50,000 cells per mL, and irradiated at 10-15 Gy. Following irradiation, the cells are plated at 100 ⁇ L in 96-well plates. On Days 1, 3, 6, 10, and 13, the medium in each well is aspirated and replaced with fresh medium.
- the quiescent healthy cells can be prepared as follows.
- IMR90 cells are washed, combined with 3 mL of TrypLE trypsin-containing reagent (Thermofisher Scientific ® , Waltham, Massachusetts) and cultured for 5 min until the cells have rounded up and begin to detach from the plate. Cells are dispersed, counted, and prepared in medium at a concentration of 50,000 cells per mL. 100 ⁇ L of the cells is plated in each well of a 96-well plate. Medium is changed on Day 13. [00238] On Day 14, candidate senolytic agents can be combined with the cells as follows. A DMSO dilution series of each test compound is prepared at 200 times the final desired concentration in a 96-well PCR plate.
- Candidate senolytic agents for testing can be cultured with the cells for 6 days, replacing the culture medium with fresh medium and the same compound concentration on Day 17.
- Candidate senolytic agents are cultured with the cells for 3 days.
- the assay system uses the properties of a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis.
- Example 3 Measuring senolytic activity of candidate senolytic agents in senescent HUVEC cells
- Human umbilical vein (HUVEC) cells from a single lot can be expanded in Vascular Cell Basal Media supplemented with the Endothelial Cell Growth Kit TM -VEGF from ATCC ® to approximately eight population doublings then cryopreserved.
- cells for the senescent population can be thawed and seeded at approximately 27,000/cm 2 . All cells are cultured in humidified incubators with 5% CO 2 and 3% O 2 and media changed every 48 hr. Two days after seeding, the cells are irradiated, delivering 12 Gy radiation from an X-ray source. Three days prior to the start of the assay, cells for the non-senescent populations are thawed and seeded as for the senescent population.
- candidate senolytic agents can be diluted from 10 mM stocks into media to provide the highest concentration working stock, aliquots of which can then be further diluted in media to provide the remaining two working stocks. To initiate the assay, 5 ⁇ L of the working stock can be added to the cell plates.
- the final test concentrations were 20, 2, and 0.2 ⁇ M.
- 100 candidate senolytic agents can be assayed in triplicate at a single concentration along with three wells of a positive control and five no treatment (DMSO) controls. Following senolytic agent addition, the plates are returned to the incubators for three days.
- Cell survival can be assessed indirectly by measuring total ATP concentration using CellTiter- Glo TM reagent (Promega ® ). The resultant luminescence was quantitated with an EnSpire TM plate reader (Perkin Elmer ® ). The relative cell viability for each concentration of a senolytic agent is calculated as a percentage relative to the no-treatment controls for the same plate.
- Senolytic agents are prepared as 10-point 1:3 dilution series in DMSO, then diluted to 12X in media. Five microliters of this working stock are then added to the cell plates. After three days of incubation, cell survival relative to DMSO control can be calculated as described above. All measurements can be performed in quadruplicate.
- Example 4 Selectivity of senolytic combinations on senescent lung epithelial cells
- primary SAEC cells in culture were covered with TrypLE trypsin-containing reagent (Thermofisher Scientific®, Waltham, Massachusetts) and incubated for 8 min until the cells rounded up and began to detach from the plate. Cells were dispersed, counted, and prepared in medium at a concentration of 94,400 cells per mL. This cell suspension was plated in 384-well plates at a volume of 25 ⁇ L per well (2360 cells/well). Within 24-hours after cell plating, the 384-well plates were irradiated at 12 Gy to generate senescent cells (SnC), as described in Example 1.
- SnC senescent cells
- control 384-well plates were processed in parallel that were not irradiated, representing normal, non-senescent cells (NsC).
- NsC normal, non-senescent cells
- candidate senolytic agents were combined with either the SnC or NsC cells as follows: (1) the Bcl-XL inhibitor Compound #B-39-1 alone and in combination with 0.25 ⁇ M of the Mcl-1 inhibitor Compound # M1-1; (2) the Bcl-XL inhibitor Compound # B-39-2 alone and in combination with 0.25 ⁇ M of the Mcl-1 inhibitor Compound # M1-1; and (3) the Bcl-XL inhibitor Compound #5 alone and in combination with 0.25 ⁇ M of the Mcl-1 inhibitor Compound # M1-1.
- a 13-pt dilution series of each senolytic (in DMSO) was prepared at 1000 times the final desired concentration in a 384-well plate.
- the DMSO stocks were diluted 1:1000 into prewarmed complete medium.
- Medium was aspirated from the cells in each well, and 25 ⁇ L/well of the senolytic containing medium was added.
- the senolytic combinations described above were spiked in across all doses using a Tecan D300e Digital Dispenser at a fixed concentration and were cultured with the cells for 3 days.
- the assay system used the properties of a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis.
- the plates were removed from the incubator and allowed to equilibrate at room temperature for 15 minutes then 25 ⁇ L of CellTiter-Glo ® reagent (Promega® Corp., Madison, Wisconsin) was added to each of the wells. The cell plates were placed for 30 seconds on an orbital shaker and then allowed to stand at room temperature for 30 minutes before measuring luminescence.
- Bcl-XL and Mcl-1 Biochemical Target Engagement Pharmacodynamics [00247] A target engagement assay to determine Bcl-XL and Mcl-1’s respective interaction with BIM both in vivo in mice, or cells in culture, in order to predict senolysis is described. The respective binding pockets of Bcl-XL and Mcl-1 proteins under normal conditions sequestrate pro-apoptotic proteins, such as BIM.
- Co-immunoprecipitation can be employed to study protein-protein interactions in order to determine if candidate senolytics can effectively displace Bcl-XL or Mcl-1 from BIM protein.
- Lysates for co-IP experiments can be prepared from: (a) lungs from mice that had been dosed for 8 hours by oral aspiration (OA) with either a candidate senolytic Bcl-XL or Mcl-1 inhibitor, or a control vehicle treatment; or (b) mouse bronchiotrachael epithelial (MBE) cells, dosed for 4 hours with the same Bcl-XL or Mcl-1 inhibitor, using a non-denaturing lysis buffer: PBS pH 7.4, 2% CHAPS, supplemented with a protease inhibitor cocktail (Roche ® )).
- OA oral aspiration
- MBE mouse bronchiotrachael epithelial
- 100 ul lysate can be incubated with 10 ⁇ L of magnetic beads (pre-coated with 2 ⁇ g of antibody) for 1 hour at 4°C in a Thermal Mixer at 1300 rpm (VWR ® ). After immunocapture, samples can be washed three times with cold lysis buffer and eluted from the beads using non-reducing NuPAGE LDS Sample Buffer ® (Life Technologies ® ). The eluted BIM co-immunoprecipitates can be separated on a NuPAGE 4–12% Bis-Tris Gel using MES running buffer (Life Technologies ® ), and transferred on a nitrocellulose membrane using the iBlot Gel Transfer System ® (Life Technologies ® ) according to the manufacturer’s instructions.
- rabbit monoclonal antibodies can be used simultaneously at 1:1000 (Cell Signaling Technology ® ; clones 54H6 and D2W9E, respectively).
- Anti-rabbit IgG, HRP-linked antibody (Cell Signaling Technology ® ) can be used as a secondary antibody at 1:10000.
- Chemiluminescence can be performed using the SuperSignal Chemiluminescence Kit ® (Pierce ® ) according to the manufacturer’s instructions and images were captured using an Azure Western Blot Imaging System ® .
- Example 6 Biochemical Potency of Bcl-XL and Mcl-1 Inhibitors
- This biochemical potency assay determines the ability of candidate senolytic inhibitors to disrupt the interaction between Bcl-XL/Mcl-1 proteins and their BH3 binding partners BAD/BIM, respectively.
- the experiment was performed over two days. On the first day, Bcl-XL inhibitors and Mcl- 1 inhibitors of the invention were diluted and incubated with BH3 peptides followed by addition of Bcl- XL/Mcl-1 proteins. Following equilibration, peptide displacement was determined the following day using AlphaLISA ® technology.
- a 15-pt, 1:3 dilution series of each senolytic (in DMSO) was prepared using a Freedom EVO 150 Liquid Handler (Tecan ® ). Senolytic compounds were assayed with 0.4 nM Bcl-XL protein (Sigma ® , Cat No. SRP0187) and 0.2 nM BAD peptide (Genscript ® ), and 0.4 nM Mcl-1 protein (In-house) was assayed with 5 nM BIM peptide (Genscript ® ). First, BAD/BIM peptide was added to diluted compound, and this was followed by Bcl-XL or Mcl-1 protein addition.
- reaction was carried out in assay buffer: 250 mM HEPES pH 7.5, 1 M NaCl, 1% BSA, 0.05% Tween-20, and the reactions were prepared in 384- well assay plates (PerkinElmer ® , Cat No.6008280). After addition of all the reagents the plates were sealed, mixed, and incubated overnight at room temperature. [00253] The next day, AlphaLISA ® acceptor beads (PerkinElmer ® Cat No. AL128M) were diluted into assay buffer and added to each reaction for 30 minutes. Subsequently, AlphaScreen ® Streptavidin donor beads were included in the reaction (PerkinElmer ® Cat No.6760002), for 30 minutes and kept in the dark.
- assay buffer 250 mM HEPES pH 7.5, 1 M NaCl, 1% BSA, 0.05% Tween-20
- Example 7 Cellular Potency of BCL and MCL inhibitors [00254] To evaluate and quantitate the cellular potency of Bcl-XL and Mcl-1 inhibitors in cells in culture or tissue, an assay was developed on the Mesoscale ® discovery (MSD ® ) platform for sensitive detection of endogenous protein interaction. In brief, cellular target engagement potency was determined through dose-responsive inhibition of Bcl-XL or Mcl-1 interaction with its BH3 binding partner BIM.
- MCF7 cells were used because of their Bcl-XL and Mcl- 1 expression levels.
- MCF7 were plated and grown on 96-well plates for at least 24 hours to near confluency. Cells were treated with an 11-pt, 1:3 dilution series of each test compound (originally in DMSO but diluted with cell culture media) that was prepared using a Freedom EVO 150 Liquid Handler (Tecan ® ).
- MSD GOLD 96-well Streptavidin SECTOR plates were prepared for protein capture by washing (PBS + 0.05% Tween-20) and blocking (MSD Blocker A) the plate according to the manufacturer’s instructions. Next, biotinylated BIM antibody was captured onto the plate for 1 hour, followed by additional washes to remove unbound antibody.
- Pre-diluted recombinant standards and lysates from candidate senolytic compound-treated MCF7 cell lysates were then added to the plate for anti-BIM capture. Following additional washes, sulfo-tagged anti-Bcl-XL or anti-Mcl-1 detection antibody was added and incubated for an additional hour. After incubation, the detection antibody solution was removed and washes repeated, followed by addition of MSD read buffer. Electro-chemiluminescent signal intensity was measured on the Meso Scale Discovery SECTOR Imager 6000.
- Example 8 Synergistic Efficacy of Senolytic Combinations on Senescent Epithelial Cells [00257]
- Results from Examples 6 and 7 suggested that both Bcl-XL and Mcl-1 needed to be displaced from binding to BIM to observe senolysis.
- Bcl-XL inhibitor and Mcl-1 inhibitor combinations were tested for their senolytic potential by performing dose-response matrices on senescent cells.
- Primary human SAECs were made senescent as described in Example 1. Fresh media was added on Day 7 and candidate senolytic combinations were added in a dose-response matrix on a 384-well plate in a 11 x 7 well format.
- Bcl-XL inhibitors were tested at the following final concentrations: 0, 0.010, 0.022, 0.046, 0.1, 0.22, 0.46, 1.00, 2.15, 4.64, 10 ⁇ M (left to right), whereas an Mcl-1 inhibitor was added at 2.50, 1.16, 0.54, 0.25, 0.12, 0.05 ⁇ M (top to bottom).
- DMSO dimethyl sulfoxide
- Tecan® D300e Digital Dispenser Tecan Life Sciences®
- Each plate also included a similar matrix in which the candidate senolytic was substituted with DMSO to serve as a viability normalization control.
- the candidate senolytics were cultured with the senescent SAECs for 3 days. On Day 10, the end of the assay period, the plates were removed from the incubator and allowed to equilibrate at room temperature for 15 minutes. Then, 25 ⁇ L of CellTiter-Glo® reagent (Promega® Corp., Madison, Wisconsin) was added to each of the wells.
- the assay system used the properties of a thermostable luciferase to enable reaction conditions that generate a stable luminescent signal while simultaneously inhibiting endogenous ATPase released during cell lysis.
- the cell plates were placed for 30 seconds on an orbital shaker and then allowed to stand at room temperature for 30 minutes before measuring luminescence.
- the delta scoring requires the parameters for the dose–response curves both in monotherapy and in combination and at least three dose–response data points.
- a delta score can be calculated for each senolytic dose combination in the matrix, which allows for a surface plot of delta scores. Such a surface plot enables one to characterize drug interaction effects over the full dose matrix, which is more informative than what a single summary score can provide.
- Example 9 Senolysis Assessment in the Idiopathic Pulmonary Fibrosis Pharmacodynamic Model
- Senescence is induced in the lungs of mice using bleomycin. Mouse lung cells are processed to enrich for lung epithelial cells.
- Epithelial cells are thought to be major contributors to the inflammation associated with human diseases. Post-bleomycin administration, Bcl-XL and Mcl-1 inhibitors are administered in combination to determine their senolytic potency towards eliminating senescent epithelial cells. Senescence can be measured using qPCR, flow cytometry and immunohistochemistry (IHC). Induction of apoptosis in senescent cells is measured by caspase and TUNEL assays as described herein. [00261] Bleomycin senescence induction: Senescence can be induced in mouse lungs using oral aspiration (OA) delivery of bleomycin. Bleomycin is a DNA damaging agent that induces senescence, inflammation and fibrosis in the lungs.
- OA oral aspiration
- Bcl-XL and Mcl-1 inhibitors are administered 7-21 days post-bleomycin induction via OA or in some instances systemic delivery (oral, intravenous, intraperitoneal). In a given experiment, Bcl-XL and Mcl-1 inhibitors are formulated at concentrations ranging from 0.1-10 mg/ml and then administered both individually and in combination with each other.
- mice are anesthetized, and the lungs are perfused with PBS and isolated for processing.
- the left lung is fixed in optimal cutting temperature (OCT) compound for IHC analysis while the right lung is processed to make a single cell suspension.
- OCT optimal cutting temperature
- right lungs are minced with scissors and then incubated in a collagenase cocktail for 1hr at 37°C. This suspension is then incubated for 5 min at room temperature with Biovision ® RBC lysis buffer.
- CD45 Depletion [00264] To remove CD45(+) immune cells, the single cell lung preps are incubated with 10% CD45(+) microbeads for 15 min at 4°C in a microtiter plate. After incubation the cells are centrifuged at 350 g for 5 min. The CD45(+) cells are removed by magnetic separation after several washes with buffer.
- EpCAM epithelial cell adhesion molecule
- IHC Immunohistochemistry
- Terminal deoxynucleotidyl transferase dUTP nick end labeling is a method for detecting DNA fragmentation by labeling the 3′-hydroxyl termini in the double-strand DNA breaks generated during apoptosis. This staining methodology can be performed to quantify apoptosis.
- qPCR RNA is isolated from CD45(-)/EpCAM(+) using standard trizol protocols. A multiplexed qPCR reaction is run using cDNA encoded from 500ng isolated RNA using the Superscript 4 kit. The PCR reaction utilizes TaqmanTM expression assays which contain primers specific for p16, TBP and actin.
- p16 is quantified using the ⁇ Ct method using actin and TATA box binding protein (TBP) as reference genes to normalize the expression levels.
- TBP TATA box binding protein
- Example 10 Efficacy of senolytic agents in a pulmonary disease model
- This example illustrates the testing of candidate senolytic combinations in a mouse model for treatment of lung disease: specifically, as a model for chronic obstructive pulmonary disease (COPD), in which mice are exposed to cigarette smoke.
- COPD chronic obstructive pulmonary disease
- the effect of candidate senolytic agents in combination on the mice exposed to smoke is assessed by senescent cell clearance, lung function, and histopathology.
- the mice to be used in this study include the 3MR strain, described in US 2017/0027139 A1 and in Demaria et al., Dev Cell. 2014 December 22; 31(6): 722–733.
- the 3MR mouse has a transgene encoding thymidine kinase that converts the prodrug gancyclovir (GCV) to a compound that is lethal to cells.
- the enzyme in the transgene is placed under control of the p16 promoter, which causes it to be specifically expressed in senescent cells. Treatment of the mice with GCV eliminates senescent cells.
- Other mice to be used in this study include the INK-ATTAC strain, described in US 2015/0296755 A1 and in Baker et al., Nature 2011 Nov 2;479(7372):232-236.
- the INK-ATTAC mouse has a transgene encoding switchable caspase 8 under control of the p16 promoter.
- the caspase 8 can be activated by treating the mice with the switch compound AP20187, whereupon the caspase 8 directly induces apoptosis in senescent cells, eliminating them from the mouse.
- six-week-old 3MR or INK-ATTAC mice can be chronically exposed to cigarette smoke generated from a Teague TE-10 system, an automatically-controlled cigarette smoking machine that produces a combination of side-stream and mainstream cigarette smoke in a chamber, which is transported to a collecting and mixing chamber where varying amounts of air is mixed with the smoke mixture.
- the COPD protocol was adapted from the COPD core facility at Johns Hopkins University (Rangasamy et al., 2004, J. Clin. Invest.
- mice can receive a total of 6 hours of cigarette smoke exposure per day, 5 days a week for 6 months.
- Each lighted cigarette (3R4F research cigarettes containing 10.9 mg of total particulate matter (TPM), 9.4 mg of tar, and 0.726 mg of nicotine, and 11.9 mg carbon monoxide per cigarette [University of Kentucky, Lexington, KY]) was puffed for 2 seconds and once every minute for a total of 8 puffs, with the flow rate of 1.05 L/min, to provide a standard puff of 35 cm 3 .
- the smoke machine can be adjusted to produce a mixture of side stream smoke (89%) and mainstream smoke (11%) by smoldering 2 cigarettes at one time.
- the smoke chamber atmosphere was monitored for total suspended particulates (80-120 mg/m 3 ) and carbon monoxide (350 ppm).
- INK-ATTAC and 3MR mice are treated with AP20187 (3x per week) or gancyclovir (5 consecutive days of treatment followed by 16 days off drug, repeated until the end of the experiment), respectively. An equal number of mice received a corresponding vehicle as control. The remaining mice are evenly split and can be placed into three different treatment groups.
- One group can receive a test Bcl-XL inhibitor in combination with a test Mcl-1 inhibitor at doses suitable for the necessary pK and PD.
- One group can receive the test Bcl-XL inhibitor alone or the test Mcl-1 inhibitor alone, and the last group can receive only the vehicle as a control, following the same treatment regimen as the test inhibitors. Additional mice that did not receive exposure to cigarette smoke were used as controls for the experiment. [00275] After two months of cigarette smoke (CS) exposure, lung function can be assessed by monitoring oxygen saturation using the MouseSTAT PhysioSuiteTM pulse oximeter (Kent Scientific). Animals are anesthetized with isoflurane (1.5%) and the toe clip is applied.
- Example 11 Efficacy of senolytic agents in an in vivo osteoarthritis model
- Candidate senolytics in combination may be tested in a mouse model for treatment of osteoarthritis as follows. C57BL/6J mice can undergo surgery to cut the anterior cruciate ligament of one rear limb to induce osteoarthritis in the joint of that limb. During week 3 and week 4 post-surgery, the mice can be treated with candidate senolytics in combination per operated knee by intra-articular injection, q.o.d. for 2 weeks.
- mice may be monitored for the presence of senescent cells, assessed for function, monitored for markers of inflammation, and histological assessment.
- Two control groups of mice can be included in the studies performed: one group comprising C57BL/6J mice that undergo a sham surgery (i.e., surgical procedures followed except for cutting the ACL) and intra-articular injections of vehicle parallel to the senolytic treated group; and one group comprising C57BL/6J mice that undergo an ACL surgery and received intra-articular injections of vehicle parallel to the senolytic-treated group.
- RNA from the operated joints of mice from the senolytic-treated mice can be analyzed for expression of SASP factors, such as, for example, IL-6, and senescence markers, such as, for example, p16.
- qRT-PCR can be performed to detect mRNA levels.
- Function of the limbs can be assessed 4 weeks post-surgery by a weight bearing test to determine which leg the treated mice favored.
- the mice can be allowed to acclimate to the chamber on at least three occasions prior to taking measurements. Mice may be maneuvered inside the chamber to stand with one hind paw on each scale.
- the weight that is placed on each hind limb can be measured over a three second period. At least three separate measurements can be made for each animal at each time point.
- Example 12 Efficacy of senolytic agents in a bleomycin-induced glaucoma model
- This example illustrates the testing of a Bcl-XL inhibitor in combination with an Mcl-1 inhibitor in a mouse model for treatment of an eye disease, specifically primary open angle glaucoma (POAG).
- POAG primary open angle glaucoma
- Male C57Bl6/J mice aged 8-10 weeks can be sedated in isofluorane chamber for 3 min then placed on operating table in a nose-cone to maintain constant isofluorane anesthesia.
- One drop of 2.5% phenylephrine-tropicamide is deposited on the eye for dilation.
- IOP intra-ocular pressure
- TonolabTM intra-ocular pressure
- the IOP value is reported as an average of six measurements.
- two ⁇ L of bleomycin (0.25U/kg) or PBS (control) can be intra-camerally injected in the right eye.
- IOP measurements can be performed at Day 7 (before treatment), 14, and 21 days after injury. Treatment can be performed 7 days after bleomycin injury. Mice can be sedated in an isofluorane chamber for 3 min then placed on operating table in a nose-cone to maintain constant isofluorane anesthesia.
- RNA extraction can be performed using chloroform extraction followed by use of the Direct- Zol MicroprepTM RNA extraction kit (VWR ® ). Five hundred nanograms of RNA can be used to prepare cDNA using the High Capacity Reverse TranscriptaseTM kit (ThermoFisher ® ).
- Efficacy of senolytic agents in an animal model of diabetes induced retinopathy [00283]
- the streptozotocin (STZ) rodent model (Feit-Leichman et al, IOVS 46:4281-87, 2005) recapitulates features of diabetic retinopathy and diabetic macular edema through the induction of hyperglycemia via the direct cytotoxic action of STZ on pancreatic beta cells.
- Hyperglycemia occurs within days following STZ administration and phenotypic aspects of diabetic retinopathy occur within weeks, with vascular leakage and reduced visual acuity and contrast sensitivity demonstrated in these rodents. This model has thus been widely used for the evaluation of therapeutic agents in diabetic eye disease.
- C57BL/6J mice of 6- to 7-weeks are weighed and their baseline glycemia are measured (Accu- Chek ® , Roche). Mice can be injected intraperitoneally with STZ (Sigma-Alderich ® , St. Lois, MO) for 5 consecutive days at 55 mg/Kg. Age-matched controls can be injected with buffer only.
- Glycemia can be measured again a week after the last STZ injection and mice are considered diabetic if their non-fasted glycemia is higher than 17 mM (300 mg/dL).
- STZ treated diabetic C57BL/6J mice can be intravitreally injected with microliter volumes of candidate senolytic agents at 8 and 9 weeks after STZ administration.
- Retinal Evans blue permeation assay can be performed at 10 weeks after STZ treatment.
- Example 14 Effect of senolytic agents in animal models of atherosclerosis
- Candidate senolytics in combination may be tested in a mouse model for treatment of atherosclerosis utilizing the LDLR -/- mice (The Jackson Laboratory), that have a Ldlr tm1Her mutation resulting in an elevated serum cholesterol level, and can be induced to have very high levels of serum cholesterol when fed a high fat diet, as follows.
- Two groups of LDLR -/- mice (10 weeks) can be fed a commercially available murine high fat diet (HFD) of Harlan Teklad TD.88137, having 42% calories from fat, beginning at Week 0 and throughout the study.
- HFD murine high fat diet
- Two groups of LDLR -/- mice (10 weeks) can be fed normal chow (-HFD). From weeks 0-2, one group of HFD mice and –HFD mice are treated with candidate senolytic agents in combination. One treatment cycle is 14 days treatment, 14 days off. Vehicle is administered to one group of HFD mice and one group of –HFD mice. At week 4 (time point 1), one group of mice are sacrificed and to assess presence of senescent cells in the plaques. For the some of the remaining mice, candidate senolytic agent treatment and vehicle administration is repeated from weeks 4-6. At week 8 (timepoint 2), the mice can be sacrificed to assess the presence of senescent cells in the plaques.
- mice are treated with candidate senolytic agents or vehicle from weeks 8-10.
- timepoint 3 the mice are sacrificed and to assess the level of plaque and the number of senescent cells in the plaques.
- Plasma lipid levels can be measured in LDLR -/- mice fed a HFD and treated with candidate senolytic agents or vehicle at time point 1 as compared with mice fed a -HFD. Plasma can be collected mid-afternoon and analyzed for circulating lipids and lipoproteins.
- Clearance of senescent cells with candidate senolytic agents in LDLR -/- mice fed a HFD can be assessed and the expression levels of several SASP factors and senescent cell markers, such as, for example, but not limited to MMP3, MMP13, PAI1, p21, IGFBP2, IL-1A, and IL-1B after 1 treatment cycle can also be measured by RT-PCR analysis.
- SASP factors and senescent cell markers such as, for example, but not limited to MMP3, MMP13, PAI1, p21, IGFBP2, IL-1A, and IL-1B after 1 treatment cycle can also be measured by RT-PCR analysis.
- aortic arches can be dissected for RT-PCR analysis of SASP factors and senescent cell markers.
- LDLR -/- mice fed a HFD and treated with candidate senolytic agents or vehicle can be sacrificed, and aortas dissected and stained with Sudan IV to detect the presence of lipid.
- Body composition of the mice can be analyzed by MRI, and circulating blood cells can be counted by an automated hematology system, HemavetTM (Drew Scientific Group).
- Example 15 Anti-fibrosis Assessment in an in vivo pulmonary fibrosis model
- a variety of different in vivo rodent models will be explored with the goal to assess effects on both relevant senescent and fibrotic factors as well as histological fibrosis.
- the models under investigation are as follows: [00290] a. Single dose bleo: Male C57Bl/6J mice at 10-14 weeks of age are subjected to a single OA of 1-2 U/kg bleomycin prepared in 50 ul PBS. Bleomycin injury is then allowed to develop for 14 to 21 days.
- senolytic compounds of the invention are dosed with senolytic compounds of the invention up to 1 dose per day at varying intervals starting from as early as day 0 and as late as up to day 17 post bleomycin dosing.
- lungs are harvested at a selected timepoint post bleomycin injury and evaluated by qPCR for expression levels of genes including, but not limited to, fibronectin, Col1a1, Timp1, Pai1, p21, p16, MMP12 and GDF15.
- lungs are harvested at a specified timepoint post bleomycin injury.
- the left lung lobe is harvested for measurement of collagen burden by hydroxyproline and the right lung is inflated with 10% formalin, embedded in paraffin and submitted for sectioning, H&E staining and assessment of fibrosis burden using a modified Ashcroft scoring method by a trained pathologist. Bronchioalveolar lavage fluid is also collected and evaluated for secreted factors, including but not limited to GDF15 and Muc5b, by ELISA.
- b. Multi dose bleo Male C57Bl/6J mice at 10-14 weeks of age are subjected to a multiple orotracheal instillations of 0.1-0.5 U/kg bleomycin prepared in 50 ul PBS up to 5 times a week for up to 2 weeks.
- Bleomycin injury is then allowed to develop for 14 to 35 days post the final dose of bleomycin.
- animals are dosed with senolytic compounds of the invention up to 1 dose per day at varying intervals starting as early as day 0 and as late as up to day 30 post the final bleomycin dose.
- senolytic compounds of the invention up to 1 dose per day at varying intervals starting as early as day 0 and as late as up to day 30 post the final bleomycin dose.
- lungs are harvested at a selected timepoint post the last bleomycin dose and evaluated by qPCR for expression levels of genes including but not limited to fibronectin, Col1a1, Timp1, Pai1, p21, p16, MMP12 and GDF15.
- lungs are harvested at a selected timepoint post the last bleomycin dose. Briefly, the left lung lobe is harvested for measurement of collagen burden by hydroxyproline and the right lung is inflated with 10% formalin, embedded in paraffin and submitted for sectioning, H&E staining and assessment of fibrosis burden using a modified Ashcroft scoring method by a trained pathologist. Bronchioalveolar lavage fluid is also collected and evaluated for secreted factors, including but not limited to, GDF15 and Muc5b by ELISA. [00292] c.
- mice Male C57Bl/6J mice at 10-14 weeks of age are subjected to a single 15Gy thoracic-targeted irradiation dose. Lung injury is then allowed to develop for 20 to 28 weeks post irradiation. During the course of injury progression, animals are dosed with senolytic compounds of the invention up to 1 dose per day at varying intervals starting as early as day 0 and as late as up to 27 weeks post the irradiation.
- lungs are harvested at a selected timepoint post irradiation and evaluated by qPCR for expression levels of genes including, but not limited to, fibronectin, Col1a1, Timp1, Pai1, p21, p16, MMP12 and GDF15.
- lungs are harvested at week 28 post irradiation. Briefly, the left lung lobe is harvested for measurement of collagen burden by hydroxyproline and the right lung is inflated with 10% formalin, embedded in paraffin and submitted for sectioning, H&E staining and assessment of fibrosis burden using a modified Ashcroft scoring method by a trained pathologist.
- Bronchioalveolar lavage fluid is also collected and evaluated for secreted factors including, but not limited, to GDF15 and Muc5b, by ELISA.
- Rat bleo Male CD (SD) rats at 10-14 weeks of age are subjected to five orotracheal instillations of 1.66 U/kg bleomycin prepared in 50 ul PBS once daily on days 1, 2,3, 6 and 7. Bleomycin injury is then allowed to develop for 21 days post the final dose of bleomycin. During the course of bleomycin injury, animals are dosed with senolytic compounds of the invention up to 1 dose per day at varying intervals starting as early as day 0 and as late as up to day 30 post the final bleomycin dose.
- lungs are harvested at a selected timepoint post the last bleomycin dose and evaluated by qPCR for expression levels of genes including, but not limited to, fibronectin, Col1a1, Timp1, Pai1, p21, p16, MMP12 and GDF15.
- lungs are harvested at a selected timepoint post the last bleomycin dose.
- the left lung lobe is harvested for measurement of collagen burden by hydroxyproline and the right lung is inflated with 10% formalin, embedded in paraffin and submitted for sectioning, H&E staining and assessment of fibrosis burden using a modified Ashcroft scoring method by a trained pathologist.
- Bronchioalveolar lavage fluid is also collected and evaluated for secreted factors including, but not limited to, GDF15 and Muc5b, by ELISA.
- Microspray bleo Male C57Bl/6J mice at 10-14 weeks of age are subjected to a single dose of 3 U/kg bleomycin prepared in 50 ul PBS and delivered by a microspray device to promote dispersal throughout the lung.
- Bleomycin injury is then allowed to develop for 14 to 21 days.
- animals are dosed with senolytic compounds of the invention up to 1 dose per day at varying intervals starting from as early as day 0 and as late as up to day 17 post bleomycin dosing.
- senolytic compounds of the invention up to 1 dose per day at varying intervals starting from as early as day 0 and as late as up to day 17 post bleomycin dosing.
- lungs are harvested at day 14 post bleomycin injury and evaluated by qPCR for expression levels of genes including, but not limited to, fibronectin, Col1a1, Timp1, Pai1, p21, p16, MMP12 and GDF15.
- lungs are harvested at day 21 post bleomycin injury.
- the post caval lobe is harvested for gene expression as described above, the left lung lobe is harvested for measurement of collagen burden by hydroxyproline and the right lung is inflated with 10% formalin, embedded in paraffin and submitted for sectioning, H&E staining and assessment of fibrosis burden using a modified Ashcroft scoring method by a trained pathologist.
- Bronchioalveolar lavage fluid is also collected and evaluated for secreted factors including, but not limited to, GDF15 and Muc5b, by ELISA.
- PCLS Human Precision Cut Lung Slices
- Human PCLS will be prepared as follows. Lungs from normal, healthy individuals or IPF patients will be gently inflated with warm 1.5% agarose-DMEM mix (Sigma ® #A6013). Afterwards, lung explants will be macroscopically assessed by an experienced pulmopathologist to identify regions of interest and exclude previously unknown medical conditions (e.g. neoplasias or infections).
- sections ( ⁇ 4-8 mm) will be sliced in cold EBSS using a Krumdieck Tissue Slicer (Alabama Research and DevelopmentSM, Munford, AL, USA) into approx.500 ⁇ m thin slices.
- PCLS will be washed thoroughly before cultivation in DMEM/F12 medium (Gibco ® , #12634) under normal immersion culture conditions (37 °C, 5% CO2, and >95% air humidity) for 5 hours for PD caspase/LDH activity measurements, or for 48h following pro-fibrotic cocktail treatment. All treatments are done with six technical replicas.
- Caspase 3/7 activity (Promega ® , #G8090) in lysates will be normalized to total protein conc.
- senescence marker p16 expression is upregulated in idiopathic pulmonary fibrosis (IPF), therefore any significant reduction of p16 expression as measured by qPCR or abundance of p16 as measured by ELISA in IPF PCLS following administration of the senolytic combinations of the invention will indicate effective senolysis. Determination of the beneficial effects of compounds of the invention on reducing the senescence burden in PCLS obtained from IPF patients will be performed as follows.
- PCLSs Upon harvest, PCLSs will be collected for staining and analysis of p16/senescence and fibrosis, or flash frozen for RNA-seq/qPCR detection of relevant markers of senescence, fibrosis and epithelial regeneration. Supernatants will be harvested for studying changes in SASP factors through Luminex® or MSD® analysis. Upon observing senolysis through p16 reduction, markers of fibrosis will be evaluated using established methodologies, including collagen level determination (picrosirius red staining) or Ashcroft scoring, and gene expression changes of fibrosis markers, such as, for example, but not limited to FN1, SERPINE1, TIMP1, COL1A1, AGR2 and MUC5B via qPCR.
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Abstract
La présente invention concerne la combinaison d'un nouvel inhibiteur de Mcl-1 avec un inhibiteur de Bcl-XL afin de traiter des maladies associées à la sénescence.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110263599A1 (en) * | 2007-04-16 | 2011-10-27 | Abbott Laboratories | 7-nonsubstituted indole mcl-1 inhibitors |
US20170174689A1 (en) * | 2014-03-27 | 2017-06-22 | Vanderbilt University | Substituted indole mcl-1 inhibitors |
US20170266211A1 (en) * | 2015-02-06 | 2017-09-21 | Unity Biotechnology, Inc. | Use of a heterocyclic bcl-2 inhibitor for removing senescent cells and treating senescence-associated conditions |
US20170305926A1 (en) * | 2016-04-22 | 2017-10-26 | Astrazeneca Ab | Mcl-1 inhibitors and methods of use thereof |
US20190240225A1 (en) * | 2016-07-22 | 2019-08-08 | Les Laboratoires Servier | Combination of a bcl-2 inhibitor and a mcl-1 inhibitor, uses and pharmaceutical compositions thereof |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110263599A1 (en) * | 2007-04-16 | 2011-10-27 | Abbott Laboratories | 7-nonsubstituted indole mcl-1 inhibitors |
US20170174689A1 (en) * | 2014-03-27 | 2017-06-22 | Vanderbilt University | Substituted indole mcl-1 inhibitors |
US20170266211A1 (en) * | 2015-02-06 | 2017-09-21 | Unity Biotechnology, Inc. | Use of a heterocyclic bcl-2 inhibitor for removing senescent cells and treating senescence-associated conditions |
US20170305926A1 (en) * | 2016-04-22 | 2017-10-26 | Astrazeneca Ab | Mcl-1 inhibitors and methods of use thereof |
US20190240225A1 (en) * | 2016-07-22 | 2019-08-08 | Les Laboratoires Servier | Combination of a bcl-2 inhibitor and a mcl-1 inhibitor, uses and pharmaceutical compositions thereof |
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