WO2015051149A1 - Analogues de sorafenib et leurs utilisations - Google Patents

Analogues de sorafenib et leurs utilisations Download PDF

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WO2015051149A1
WO2015051149A1 PCT/US2014/058869 US2014058869W WO2015051149A1 WO 2015051149 A1 WO2015051149 A1 WO 2015051149A1 US 2014058869 W US2014058869 W US 2014058869W WO 2015051149 A1 WO2015051149 A1 WO 2015051149A1
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group
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alkyl
mmol
cancer
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Brent R. Stockwell
Scott J. Dixon
Rachid SKOUTA
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The Trustees Of Columbia University In The City Of New York
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention provides, inter alia, compounds according formula I:
  • compositions and kits containing such compounds and methods for using such compounds, compositions, and kits.
  • System x c is a cell-surface Na + -independent cystine/glutamate antiporter composed of the 12-pass transmembrane transporter protein SLC7A1 1 (xCT) linked via a disulfide bridge to the single-pass transmembrane regulatory subunit SLC3A2 (4F2hc, CD98hc) (Sato et al., 1999, Conrad and Sato, 2012).
  • System x c " is essential for normal mammalian plasma redox homeostasis, pigmentation, immune system function and memory formation (Chintala et al., 2005, Sato et al., 2005, De Bundel et al., 201 1 ). When dysregulated, system x c " is also implicated in tumorigenesis, cancer stem cell maintenance, drug resistance and neurological dysfunction (Okuno et al., 2003, Buckingham et al., 201 1 , Ishimoto et al., 201 1 , Yae et al., 2012).
  • Erastin and RSL3 are small molecules that trigger a non- apoptotic form of cell death in mammalian cells, termed ferroptosis, that is characterized by the iron-dependent accumulation of intracellular reactive oxygen species (ROS) (Dolma et al., 2003, Yagoda et al., 2007, Yang and Stockwell, 2008, Dixon et al., 2012).
  • ROS reactive oxygen species
  • erastin-induced cell death was strongly suppressed by beta-mercaptoethanol ( ⁇ - ⁇ ) (Dixon et al., 2012), which forms mixed disulfides with extracellular cystine that are imported into cells by non-system-x c " transporters (Ishii et al., 1981 ), effectively circumventing the need for system x c " for cell survival.
  • ⁇ - ⁇ beta-mercaptoethanol
  • RSL3-induced death was not suppressed by ⁇ - ⁇ and RSL3 did not inhibit cystine import, indicating that it acts on a distinct target (Dixon et al., 2012).
  • erastin like SAS inhibits system x c " function to trigger death.
  • one embodiment of the present invention is a compound according to formula I:
  • Ri, R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula I is not sorafenib,
  • composition comprises a pharmaceutically acceptable salt or diluent and a compound according to formula I:
  • Ri, R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R 11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula I is not sorafenib,
  • a further embodiment of the present invention is a kit.
  • This kit comprises any compound disclosed herein together with instructions for the use of the compound.
  • kits comprises any pharmaceutical composition disclosed herein together with instructions for the use of the pharmaceutical composition.
  • An additional embodiment of the present invention is a method for treating a subject having dysregulated system x c " activity. This method comprises administering to the subject an effective amount of a compound according to formula I:
  • Ri , R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • Rii is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-I2 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a method for treating a subject having dysregulated system x c " activity. This method comprises administering to the subject an effective amount of any pharmaceutical composition disclosed herein.
  • a further embodiment of the present invention is a method of activating ferroptosis in a cell. This method comprises administering to the cell an effective amount of a compound according to formula I:
  • Ri , R2, R3, R 4 , and R 6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R 5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • R 8 is NH or no atom
  • R 9 is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci- alkyl, halo, and combinations thereof;
  • R-io is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a method of inhibiting system x c " in a cell. This method comprises administering to the cell an effective amount of a compound according to formula I:
  • Ri , R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl
  • R 8 is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl;
  • R12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • An additional embodiment of the present invention is a method for monitoring treatment of a subject having system x c " dysregulation. This method comprises: (a) measuring the expression level of a CHAC1 gene in a subject being treated with an amount of any compound or pharmaceutical composition disclosed herein, wherein increased expression levels of the CHAC1 gene relative to a control indicate that the cells of the subject are undergoing cystine limitation; and
  • Figure 1 shows cell death triggered by ferroptosis inducers in multicellular tumor spheres (MCTSs).
  • Figures 1 C-1 F show the relative viability of MCTSs formed over 72 hours from HT-1080 (C), Calu-1 (D), A549 (E) or HCT-1 16 (F) cells in response to erastin, RSL3 or staurosporine (STS) +/- ⁇ - ⁇ or ferrostatin-1 (Fer-1 ).
  • FIG. 1 G-I show cell growth and glutamate release in oncogenic RAS-mutant cell lines.
  • G,H Relative (G) and absolute (H) glutamate release was quantified in A549, HCT- 1 16 and Calu-1 cells.
  • G,H Relative (G) and absolute (H) glutamate release was quantified in A549, HCT- 1 16 and Calu-1 cells.
  • Figure 2 shows that erastin inhibits system x c " function potently and specifically.
  • Figures 2A and 2B show Na+-independent uptake of 14 C- cystine (A) and 14 C-L-phenylalanine (B) uptake over five minutes in HT-1080 and Calu-1 cells treated with erastin or SAS. D-Phe is included as a positive control in B.
  • Figure 2C shows glutamate release +/- erastin in HT-1080 cells where SLC7A11 was silenced for 48 hours using two independent siRNAs.
  • Figure 2D shows SLC7A11 mRNA levels assayed using RT-qPCR in si- SL C7/477-transfected cells.
  • Figure 2E shows dose-response analysis of glutamate release from HT-1080 and Calu-1 cells in response to erastin and SAS.
  • Figures 2G-I show monitoring system x c ⁇ activity by following glutamate release.
  • Figure 2G shows an overview of the assay design. Glutamate released by the cell is detected by an enzyme-linked reaction. Erastin and SAS inhibit glutamate release from system x c " , but not other transporters. System x c " is one of several transporters that can release glutamate, including system X A G and others.
  • Figure 2H shows SLC7A5 expression was silenced in HT-1080 cells for 48 hours using two independent siRNAs and then glutamate release was assayed +/- erastin.
  • Figure 2I shows SLC7A5 mRNA levels in HT-1080 transfected as in 2H. Data in 2H and 2I represent mean +/-SD from three independent biological replicates.
  • Figure 3 shows inhibition of system x c " by erastin is necessary for lethality.
  • Figure 3A shows structure and lethal potency (EC50 in HT-1080 cells) of erastin and the inactive erastin analog erastin-A8.
  • Figure 3B shows dose-dependent inhibition of glutamate release by erastin and erastin-A8 (Era-A8).
  • Figure 3C shows total glutathione (GSH+GSSG) quantified by biochemical assay in HT-1080 cells treated with DMSO, erastin or erastin-A8 (Era-A8).
  • Figure 3D shows total glutathione (GSH+GSSG) levels in HT-1080 cells treated with compound combinations as indicated.
  • Figure 3E shows viability of HT-1080 cells in response to different compound combinations measured by Trypan blue exclusion.
  • Data in Figures 3B-E are from three independent biological replicates and represent mean+/-SD.
  • Figures 3F-H show the role of glutathione in ferroptosis.
  • Figure 3F shows a cartoon model of the predicted ferroptotic pathway.
  • Erastin or SAS can inhibit the function of system x c " , thereby depleting the cell of cysteine and, ultimately, reduced glutathione (GSH), allowing for the accumulation of lethal lipid ROS. Lipid ROS accumulation and ferroptotic death is prevented by Fer-1 , downstream of GSH. L-buthionine sulfoximine (BS) inhibits the first enzyme in the GSH synthetic pathway.
  • Figure 3G shows total glutathione levels measured in HT-1080 cells. Cells were treated with DMSO or BSO for 30 hours or, as an internal control, DMSO or erastin for 5 hours.
  • Figure 3H shows cell viability measured by Trypan blue exclusion 48 or 96 hours after drug treatment.
  • Figure 4 shows structure activity relationship (SAR) analysis of erastin.
  • Figure 4A shows structures of 20 erastin analogs.
  • Figure 4B shows lethal EC50 for each analog determined in HT-1080 cells in a 10-point, 2-fold dilution assay, starting at a high dose of 20 ⁇ , +/- ⁇ - ⁇ .
  • Data represent mean and 95% confidence interval (95% CI) from three independent biological replicate experiments. Also reported are IC50 values for inhibition of glutamate release as determined in CCF-STTG1 cells. These data represent the average of two experiments. All values are in ⁇ . ND: not determined.
  • Figure 5 shows analysis of erastin effects using RNA-Seq.
  • Figures 5A and 5B show lists of genes upregulated (A) and downregulated (B) by erastin treatment, as detected in HT-1080 cells using RNA-Seq. The number of fragments per kilobase of exon per megabase of sequence (FPKM) were counted and are expressed as a fold-change ratio between the different conditions.
  • E/D Erastin/DMSO expression ratio.
  • ⁇ + ⁇ - ⁇ /D Erastin+ ⁇ - ME/DMSO ratio.
  • ATP6V1G2 * ATP6V1 G2-DDX39B read-through transcript. Data represent the average of two independent biological replicates for each condition.
  • Figure 5E shows CHAC1 mRNA levels in 13 different erastin- sensitive cell lines treated with erastin or STS (6 hours).
  • Figures 5F-H show regulation of CHAC1 expression.
  • Figure 5F shows Chad mRNA levels assessed by RT-qPCR in SV40-transformed MEFs treated for 6 hours with erastin or thapsigargin (a positive control for ER stress), as indicated.
  • Figure 5G shows CHAC1 mRNA levels in HT-1080 cells treated with DMSO or erastin (10 ⁇ ) for 6 hours or DMSO or buthionine sulfoximine (BSO, 2.5 mM) for 30 hours +/- actinomycin D (Act D) or cycloheximide (CHX).
  • Figure 5H shows CHAC1 mRNA levels in HT-1080 cells treated for 6 hours with compounds as indicated.
  • Data in Figures 5F and 5G represent mean+/-SD from two independent biological replicates and data in Figure 5H represents mean+/-SD from three independent biological replicates.
  • Figure 6 shows the identification of sorafenib as an inhibitor of system x c " .
  • Figures 6A and 6B show the modulatory profiling of (A) A549 and (B) HCT-1 16 cells in response to either buthionine sulfoximine (BSO) or erastin +/- 20 different lethal compounds.
  • Figure 6C shows the viability of HT- 1080 cells treated for 24 hours with ferroptosis inhibitors ( ⁇ - ⁇ , Fer-1 , DFO) +/- sorafenib, erastin or STS.
  • Figure 6D shows the quantification of the inhibition of glutamate release by sorafenib, erastin and imatinib +/- Fer-1 .
  • Figure 6E shows the viability of HT-1080 cells treated for 24 hours with erastin, sorafenib, nilotinib, masitinib or imatinib +/- ⁇ - ⁇ or Fer-1 .
  • Cell viability in Figures 6C and 6E was quantified by Alamar blue.
  • Figure 6D none of the comparisons between DMSO and Fer-1 treated samples were significant (P > 0.05).
  • Figure 7 shows structure-activity relationship (SAR) analysis of sorafenib.
  • Figure 7A shows the structure of Sorafenib (compound 23) and thirteen sorafenib analogs (compounds 24-36). These compounds were prepared and tested in HT-1080 cells for the induction of cell death (EC50) and the suppression of this cell death (death suppression, DS) by ⁇ - ⁇ (18 ⁇ ) and ferrostatin-1 (Fer-1 , 1 ⁇ ) over 48 hours. DS values are expressed as a percentage relative with the level of suppression observed with sorafenib (compound 23) treatment, which was set to 100%. All values are means from three independent biological replicates.
  • Figure 7B shows glutamate release in response to sorafenib and select analogs.
  • Figure 7C shows the DEVDase (caspase-3/7) activity in response to sorafenib and select analogs as measured by the cleavage of a fluorescent rhodamine substrate.
  • Figure 8 shows a summary of adverse events reported with sorafenib and other kinase inhibitors. Analysis of adverse events across 20 physiological system categories associated with kinase inhibitor treatment. DETAILED DESCRIPTION OF THE INVENTION
  • One embodiment of the present invention is a compound according to formula I:
  • Ri , R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • Rii is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-I2 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula I is not sorafenib,
  • halo and halogen are used interchangeably herein and mean halogen and include chloro, fluoro, bromo, and iodo.
  • alkyi refers to the radical of saturated aliphatic groups, including straight-chain alkyi groups, branched-chain alkyi groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C1 -C10 for straight chains, C3-C10 for branched chains).
  • the alkyl has from 1 -4 carbon atoms.
  • certain cycloalkyls have from 3-8 carbon atoms in their ring structure, including 5, 6 or 7 carbons in the ring structure.
  • C x-y when used in conjunction with a chemical moiety, such as, alkyl, alkenyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
  • Carbonyls include without limitation, aldehydes, ketones, carboxylic acids, esters, and amides.
  • aryl as used herein includes single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 3- to 8-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • heteroaryl includes aromatic single ring structures, preferably 3- to 8-membered rings, more preferably 5- to 7-membered rings, even more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (i.e., atoms other than C, such as, e.g., N, S, or O), preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroatom i.e., atoms other than C, such as, e.g., N, S, or O
  • heteroaryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, benzothiazole, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • hydroxyl or "hydroxy,” as used herein, refers to the group -OH.
  • heterocyclyl refers to non-aromatic ring structures, preferably 3- to 8-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms, i.e., atoms other than C, such as, e.g., N, S, or O.
  • heterocyclyl also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • amide or “amido”, as used herein, refers to a group
  • R 4 and Ri 5 each independently represent a hydrogen or a Ci- alkyl group.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy and the like.
  • Other alkoxy groups within the scope of the present invention include, for example, the following:
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
  • Ri , Ri 5 , and R15 each independently represent a hydrogen or a Ci -4 alkyl group.
  • the term "primary" amine means only one of Ri 4 and R15, or one of Ri 4 , R15, and R15' is an alkyl group. Secondary amines have two alkyl groups bound to N. In tertiary amines, all three groups, Ri 4 , R15, and R15 , are replaced by alkyl groups.
  • carbocycle refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
  • the ring may be monocyclic, bicyclic, tricyclic, or even of higher order.
  • carbocycle encompass fused, bridged and spirocyclic systems:
  • a carbocycle ring contains from 3 to 14 atoms, including 3 to 8 or 5 to 7 atoms, such as for example, 6 atoms.
  • diol is art-recognized and refers to molecules that
  • N-oxide refers to a compound containing a N + -O " functional group.
  • crystalline form refers to the crystal structure of a compound of the present invention.
  • a compound may exist in one or more crystalline forms, which may have different structural, physical, pharmacological, or chemical characteristics. Different crystalline forms may be obtained using variations in nucleation, growth kinetics, agglomeration, and breakage. Nucleation results when the phase-transition energy barrier is overcome, thereby allowing a particle to form from a supersaturated solution. Crystal growth is the enlargement of crystal particles caused by deposition of the chemical compound on an existing surface of the crystal. The relative rate of nucleation and growth determine the size distribution of the crystals that are formed.
  • thermodynamic driving force for both nucleation and growth is supersaturation, which is defined as the deviation from thermodynamic equilibrium.
  • Agglomeration is the formation of larger particles through two or more particles (e.g., crystals) sticking together and forming a larger crystalline structure.
  • hydrates refers to a solid or a semisolid form of a chemical compound containing water in a molecular complex.
  • the water is generally in a stochiometric amount with respect to the chemical compound.
  • the compound has the structure of formula (II):
  • R 2 and R3 are independently selected from the group consisting of H, halo, and CF 3 ;
  • R is H or halo
  • R10 is O or Ci -4 alkyl
  • A is C or N
  • B is O or S
  • R12 is selected from the group consisting of no atom, amide, CN, and heteroaryl
  • R-I 3 is selected from the group consisting of no atom or CN, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula II is not sorafenib.
  • the compounds has the structure of formula (III):
  • R 2 and R3 are independently selected from the group consisting of H, halo, and CF 3 ;
  • R10 is O or Ci -4 alkyl
  • A is C or N
  • R12 is selected from the group consisting of no atom, amide, CN, and heteroaryl
  • R-I 3 is selected from the group consisting of no atom or CN, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula II is not sorafenib.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • composition comprises a pharmaceutically acceptable salt or diluent and a compound according to formula I:
  • Ri , R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl
  • R-12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof, with the proviso that formula I is not sorafenib,
  • kits comprise any compound or pharmaceutical composition disclosed herein together with instructions for the use of the compound or pharmaceutical composition.
  • the kits of the invention may also include suitable storage containers, e.g., ampules, vials, tubes, etc., for each compound or pharmaceutical composition and other reagents, e.g., buffers, balanced salt solutions, etc., for use in administering the compound or pharmaceutical compositions to subjects.
  • the compounds, pharmaceutical compositions and other reagents may be present in the kits in any convenient form, such as, e.g., in a solution or in a powder form.
  • the kits may further include a packaging container, optionally having one or more partitions for housing the pharmaceutical composition and other optional reagents.
  • An additional embodiment of the present invention is a method for treating a subject having dysregulated system x c " activity. This method comprises administering to the subject an effective amount of a compound according to formula I:
  • Ri , F3 ⁇ 4, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl
  • R 8 is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl;
  • R12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • the compound of formula I is not sorafenib
  • a "s ubject" is a mammal, preferably, a human or a primate and more preferably, a human.
  • categories of mammals within the scope of the present invention include, for example, farm animals, domestic animals, laboratory animals, etc.
  • farm animals include cows, pigs, horses, goats, etc.
  • domestic animals include dogs, cats, etc.
  • laboratory animals include rats, mice, rabbits, guinea pigs, etc.
  • the terms "treat,” “treating,” “treatment” and grammatical variations thereof mean subjecting an individual subject to a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject, e.g., a patient.
  • the methods and compositions of the present invention may be used to slow the development of disease symptoms or delay the onset of the disease or condition, or halt the progression of disease development.
  • every treated subject may not respond to a particular treatment protocol, regimen, process or remedy, treating does not require that the desired physiologic response or outcome be achieved in each and every subject or subjects, e.g., patient population. Accordingly, a given subject or a patient population may fail to respond or respond inadequately to treatment.
  • system x c " "dysregulation” means abnormal or impaired functioning of the system x c " , which is an amino acid antiporter that typically mediates the exchange of extracellular L-cystine and intracellular L- glutamate across the cellular plasma membrane.
  • the system x c ⁇ dysregulation may be implicated in the following disease states or conditions: tumorigenesis, cancer stem cell maintenance, drug resistance, and neurological dysfunction.
  • an "effective amount” or a “therapeutically effective amount” of a compound or pharmaceutical composition disclosed herein is an amount of such compound or composition that is sufficient to effect beneficial or desired results as described herein when administered to a subject.
  • Effective dosage forms, modes of administration, and dosage amounts may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered, the age, size, and species of mammal, e.g., human patient, and like factors well known in the arts of medicine and veterinary medicine.
  • a suitable dose of a compound or pharmaceutical composition according to the invention will be that amount of the compound or pharmaceutical composition, which is the lowest dose effective to produce the desired effect.
  • the effective dose of a compound or pharmaceutical composition of the present invention may be administered as two, three, four, five, six or more sub-doses, administered separately at appropriate intervals throughout the day.
  • tumorgenesis refers to the formation or production of tumors or cancers.
  • cancer stem cell “maintenance” refers to the ability of cancer stem cells to continually retain those properties that are typically associated with normal stem cells, such as self-renewal and differentiation. Like normal stem cells, cancer stem cells have varying degrees of potency, including, but not limited to, pluripotency, and can give rise to numerous differentiated cell types, leading to the heterogeneity observed in many tumors.
  • Non-limiting examples of solid tumors and cancers include adrenocortical carcinoma, anal tumor/cancer, bladder tumor/cancer, bone tumor/cancer (such as osteosarcoma), brain tumor, breast tumor/cancer, carcinoid tumor, carcinoma, cervical tumor/cancer, colon tumor/cancer, endometrial tumor/cancer, esophageal tumor/cancer, extrahepatic bile duct tumor/cancer, Ewing family of tumors, extracranial germ cell tumor, eye tumor/cancer, gallbladder tumor/cancer, gastric tumor/cancer, germ cell tumor, gestational trophoblastic tumor, head and neck tumor/cancer, hypopharyngeal tumor/cancer, islet cell carcinoma, kidney tumor/cancer, laryngeal tumor/cancer, leukemia, lip and oral cavity tumor/cancer, liver tumor/cancer, lung tumor/cancer, lymphoma, malignant mesothelioma, Merkel cell carcinoma, mycosis
  • the subject has a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, bone cancer, colorectal cancer, lung cancer, pancreatic cancer, bladder cancer, skin cancer, liver cancer, lymphoma, and leukemia.
  • a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, bone cancer, colorectal cancer, lung cancer, pancreatic cancer, bladder cancer, skin cancer, liver cancer, lymphoma, and leukemia.
  • drug resistance refers to a reduction in efficacy of a drug being used to treat a disease or condition.
  • examples of drugs for which individuals can develop drug resistance include, but are not limited to, antineoplastics, antibiotics, antimicrobials, and antivirals.
  • Non-limiting examples of neurological dysfunction include but are not limited to multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydehann chorea, Gilles de la Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, an inflammatory retinal disease or disorder, an inflammatory ocular disease or disorder, and optic neuritis.
  • multiple sclerosis Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome,
  • Suitable and preferred compounds for use in this method are as disclosed herein.
  • the method further comprises administering at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, and combinations thereof.
  • at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, and combinations thereof.
  • an "antibody” encompasses naturally occurring immunoglobulins as well as non-naturally occurring immunoglobulins, including, for example, single chain antibodies, chimeric antibodies (e.g., humanized murine antibodies) and heteroconjugate antibodies (e.g., bispecific antibodies), as well as antigen-binding fragments thereof, (e.g., Fab', F(ab')2, Fab, Fv, and rlgG). See also, e.g., Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, III.); Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York (1998).
  • antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies.
  • antibody further includes both polyclonal and monoclonal antibodies.
  • examples of antibodies used as therapeutics include rituximab (Rituxan), Cetuximab (Erbitux), bevacizumab (Avastin), and Ibritumomab (Zevalin).
  • Cytotoxic agents may be DNA damaging agents, antimetabolites, anti-microtubule agents, antibiotic agents, etc.
  • DNA damaging agents include alkylating agents, intercalating agents, and enzyme inhibitors of DNA replication.
  • Non-limiting examples of DNA alkylating agents include cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan, temozolomide, cisplatin, carboplatin, oxaliplatin, a pharmaceutically acceptable salt thereof, a prodrug thereof, and combinations thereof.
  • the DNA alkylating agent is temozolomide, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • intercalating agents include doxorubicin, daunorubicin, idarubicin, and mitoxantrone.
  • enzyme inhibitors of DNA replication include irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide.
  • Antimetabolites include folate antagonists such as methotrexate and premetrexed, purine antagonists such as 6-mercaptopurine, dacarbazine, and fludarabine, and pyrimidine antagonists such as 5- fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, and decitabine.
  • Anti-microtubule agents include without limitation vinca alkaloids, paclitaxel (Taxol®), docetaxel (Taxotere®), and ixabepilone (Ixempra®).
  • Antibiotic agents include without limitation actinomycin, anthracyclines, valrubicinepirubicin, bleomycin, plicamycin, and mitomycin.
  • Cytotoxic agents also include erastin, RSL3, and analogs of erastin or RSL3 and pharmaceutically acceptable salts of erastin and RSL3.
  • analogs means those compounds that are structurally similar. Non-limiting examples of erastin analogs are disclosed herein and are disclose in U.S. Patent No. 8,518,959 to Becklin et al.
  • toxin refers to an antigenic poison or venom of plant or animal origin.
  • An example is diphtheria toxin or portions thereof.
  • radionuclide refers to a radioactive substance administered to the patient intravenously or orally, after which it penetrates via the patient's normal metabolism into the target organ or tissue, where it delivers local radiation for a short time.
  • radionuclides include, but are not limited to, 1-125, At-21 1 , Lu-177, Cu-67, 1-131 , Sm-153, Re-186, P-32, Re-188, ln-1 14m, and Y-90.
  • immunomodulator refers to a substance that alters the immune response by augmenting or reducing the ability of the immune system to produce antibodies or sensitized cells that recognize and react with the antigen that initiated their production.
  • Immunomodulators can be recombinant, synthetic, or natural preparations and include cytokines, corticosteroids, cytotoxic agents, thymosin, and immunoglobulins. Some immunomodulators are naturally present in the body, and certain of these are available in pharmacologic preparations.
  • immunomodulators include, but are not limited to, granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria, IL-2, IL- 7, IL-12, CCL3, CCL26, CXCL7, synthetic cytosine phosphate-guanosine (CpG), and oligodeoxynucleotides.
  • G-CSF granulocyte colony-stimulating factor
  • interferons imiquimod and cellular membrane fractions from bacteria
  • IL-2 granulocyte colony-stimulating factor
  • imiquimod and cellular membrane fractions from bacteria IL-2, IL- 7, IL-12, CCL3, CCL26, CXCL7
  • CpG synthetic cytosine phosphate-guanosine
  • oligodeoxynucleotides synthetic cytosine phosphate-guanosine
  • radiosensitizing agent refers to a compound that makes tumor cells more sensitive to radiation therapy.
  • radiosensitizing agents include misonidazole, metronidazole, tirapazamine, and trans sodium crocetinate.
  • hormone refers to a substance released by cells in one part of a body that affects cells in another part of the body.
  • hormones include, but are not limited to, prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, antimullerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, corticotropin- releasing hormone, encephalin, endothelin, erythropoietin, follicle-stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing hormone, growth hormone-releasing hormone, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin,
  • These hormone-interfering compounds include, but are not limited to, tamoxifen (Nolvadex®), anastrozole (Arimidex®), letrozole (Femara®), and fulvestrant (Faslodex®).
  • Another embodiment of the present invention is a method for treating a subject having dysregulated system x c " activity. This method comprises administering to the subject an effective amount of any pharmaceutical composition disclosed herein.
  • the method further comprises administering at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, and combinations thereof.
  • additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, and combinations thereof.
  • Suitable and preferred thereapeutic agents are as disclosed herein.
  • a further embodiment of the present invention is a method of activating ferroptosis in a cell. This method comprises administering to the cell an effective amount of a compound according to formula I:
  • Ri, R2, R3, R4, and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • Rs is NH or no atom
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • R10 is no atom, O, or Ci -4 alkyl
  • R11 is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl;
  • R12 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • ferropttosis means regulated cell death that is iron-dependent. See, e.g., Dixon et al., 2012. Ferroptosis is characterized by the overwhelming, iron-dependent accumulation of lethal lipid reactive oxygen species. Ferroptosis is distinct from apoptosis, necrosis, and autophagy. Assays for ferroptosis are as disclosed herein, for instance, in the Examples section.
  • Another embodiment of the present invention is a method of inhibiting system x c " in a cell. This method comprises administering to the cell an effective amount of a compound according to formula I:
  • Ri , R 2 , R3, R 4 , and R6 are independently selected from the group consisting of H, halo, CF 3 , OCF 3 , Ci -4 alkyl, and CN;
  • R5 is independently selected from the group consisting of no atom, NH, O, and Ci -4 alkyl;
  • R 7 is selected from the group consisting of no atom, carbonyl, thiocarbonyl, and sulfonyl;
  • R 8 is NH or no atom;
  • Rg is an aryl or heteroaryl optionally substituted with a moiety selected from the group consisting of H, hydroxy, Ci -4 alkyl, halo, and combinations thereof;
  • Rio is no atom, O, or Ci -4 alkyl
  • Rii is selected from the group consisting of no atom, aryl, heterocycle, and heteroaryl optionally substituted with a halo or a Ci -4 alkyl;
  • R-I2 is selected from the group consisting of no atom, amide, CN, heteroaryl, O, Ci -4 alkoxy, and amine;
  • R-I 3 is selected from the group consisting of no atom, alkoxy, amine, CN, carboxy, carbocyclyl optionally substituted with d- 4alkyl, diol; and the dotted line ( ) is an optional double bond, or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
  • An additional embodiment of the present invention is a method for monitoring treatment of a subject having system x c " dysregulation. This method comprises:
  • the phrase "measuring the expression level” refers to the use of those methods recognized in the art for measuring the expression level of one or multiple genes. These methods include, but are not limited to, RNA-seq (whole transcriptome shotgun sequencing), microarrays, and RT-qPCR.
  • RNA-seq whole transcriptome shotgun sequencing
  • microarrays microarrays
  • RT-qPCR RT-qPCR
  • EDIPA diisopropylethyl amine
  • EtOAc ethyl acetate
  • Et 2 O diethyl ether
  • MeOH methanol
  • EtOH ethanol
  • Na 2 SO 4 sodium sulfate
  • MgSO4 magnesium sulfate
  • DMAP 4-dimethylaminopyridine
  • POCI3 phosphorous oxychloride
  • NaHCO3 sodium bicarbonate
  • TBS-CI tert- butylchlorodimethylsilane
  • NBS N-bromosuccinimide
  • NaBH sodium borohydride
  • NH CI ammonium chloride
  • TFA triflouroacetic acid
  • PBr 3 phosphours tribromide
  • HBTU O-(Benzotriazol-1 -yl)
  • N-phenylethanamide Acetyl chloride (0.916 mL, 12.89 mmol, 1 .2 eq) was added slowly to a solution of EDIPA (2.25 mL, 12.89 mmol, 1 .2 eq) and aniline (0.98 mL, 10.74 mmol) at 0°C. The resulting mixture was stirred for an additional hour at 0°C then at 25°C for 4 hours. Upon completion, the mixture was quenched with saturated aqueous NaHCO 3 and extracted 3 times with EtOAc. The combined organic layers were dried (Na 2 SO ), concentrated, and the crude material was purified by combi flash 0- > 20% EtOAc in hexanes to provide N-phenylethanamide (1 .27 g, 88% yield).
  • Pd(PPh 3 ) 4 (187 mg, 0.162 mmol, 10%) was added to a solution of 3-((tert-butyldimethylsilyloxy)methyl)-2-chloroquinoline (0.5 g, 1 .62 mmol) in dioxane (10 mL) and stirred for 10 min at 25°C.
  • PBr 3 (0.130 ml_, 1 .38 mmol, 3 eq) was added to a solution of (2- (2-isopropoxyphenyl)quinolin-3-yl)methanol (135 mg, 0.45 mmol) in DCM (5 ml_) at 0°C. The resulting mixture was stirred at 0°C for an additional 30 minutes, then at 25°C for 2 hours. Upon completion, the reaction was quenched with saturated aqueous NaHCO 3 and extracted 3 times with EtOAc.
  • Pd(PPh 3 ) 4 (10%), 2-lsopropoxyphenylboronic acid (1.5 eq) in EtOH, NaC0 3 (2M, aq) (10.0 eq), dioxane 25°C to 80°C, 24 hr; (e) HF-py (xs), 25°C, 6 hr; (f) DMP (1.8 eq), NaHC0 3 (10 eq), CH 2 CI 2 , 25°C, 3 hr; (g) piperazine (10.0 eq), ZnCI 2 (0.2 eq),
  • TBS-CI (1 .66 g, 1 1 .04 mmol, 1 .2 eq) was added to a solution of (1 H-indol-2-yl)methanol (1 .335 g, 9.2 mmol) and EDIPA (2.4 mL, 13.8 mmol, 1 .5 eq) in DMF (30 mL) at 25°C. The mixture was stirred for an additional 5 hours at 25°C. Upon completion, the reaction contents were diluted with water and extracted 3 times with Et 2 O.
  • Dess-Martin periodinane (230 mg, 0.543 mmol, 1 .8 eq) was added to a stirred suspension of sodium bicarbonate (242 mg, 2.88 mmol, 10.0 eq) and tert-butyl 2-(hydroxymethyl)-3-(2-isopropoxyphenyl)-1 H-indole-1 - carboxylate (1 10 mg, 0.288 mmol) in DCM (3 mL). The mixture was stirred at 25°C for 2 hours, and upon completion a saturated aqueous solution of sodium sulfite (1 mL) was added, and the mixture was stirred for an additional 5 minutes. This was followed subsequently by the addition of water and extraction with DCM three times.
  • 35MEW26 was prepared from 3-(2-isopropoxyphenyl)-2- ((methyl(2(methylamino)ethyl)amino)methyl)quinazolin-4(3H)-one (20 mg, 22% yield).
  • 35MEW27 was prepared from 3-(2-isopropoxyphenyl)-2- ((methylamino)methyl)quinazolin-4(3H)-one using general acyl chloride addition procedure (71 mg, 72% yield). Mixture of atropeisomers 1 H NMR (400 MHz, chloroform-d) ⁇ 8.31 p.p.m.
  • HBTU 147 mg, 0.38 mmol, 1 .5 eq
  • 3-chlorophenoxy acetic acid 69 mg, 0.336 mmol, 1 .3 eq
  • EDIPA 67 uL, 0.38 mmol, 1 .5 eq
  • DCM 3 mL
  • a solution of 3-(2-isopropoxyphenyl)-2-(piperazin-1 -ylmethyl)quinazolin-4(3H)- one 100 mg, 0.258 mmol
  • DCM 1 mL
  • 35MEW39 was prepared using the general amine coupling procedure from 3-(2-isopropoxyphenyl)-2-(piperazin-1 -ylmethyl)quinazolin- 4(3H)-one, (132 mg, 96% yield).
  • 1 H NMR 400 MHz, chloroform-d
  • 35MEW13 was prepared using the general amine coupling procedure from 3-(2-isopropoxyphenyl)-2-(piperazin-1 -ylmethyl)quinazolin- 4(3H)-one (18 mg, 44% yield).
  • 15MEW81 was prepared using the general amine coupling procedure from 3-(2-isopropoxyphenyl)-2-(piperazin-1 -ylmethyl)quinazolin- 4(3H)-one (226 mg, 58% yield).
  • 35MEW28 was prepared using a general Suzuki coupling procedure from 21MEW26 (30 mg, 77% yield).
  • 1 H NMR 400 MHz, chloroform-d
  • 35MEW29 was prepared using a general Suzuki coupling procedure from 21MEW26 (65 mg, 54%).
  • 1 H NMR 300 MHz, chloroform-d
  • 14MEW31 was prepared from 5-chloro-3-(2-isopropoxyphenyl)- 2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one using a general acyl chloride addition procedure (122 mg, 87% yield).
  • 1 H NMR 300 MHz, chloroform-d) ⁇ 7.70-7.59 p.p.m.
  • 14MEW32 was prepared from 8-chloro-3-(2-isopropoxyphenyl)- 2-(piperazin-1 -ylmethyl)quinazolin-4(3H)-one using a general acyl chloride addition procedure (77 mg, 55% yield).
  • 13MEW16 was prepared from 3-(3-isopropoxyphenyl)-2- (piperazin-1 -ylmethyl)quinazolin-4(3H)-one using a general acyl chloride addition procedure (100 mg, 54%).
  • 13MEW76 was prepared from 3-(2-isopropoxyphenyl)-2- (piperazin-1 -ylmethyl)quinazolin-4(3H)-one using a general acyl chloride addition procedure (270 mg, 62% yield).
  • 21MEW26 was prepared from 3-(5-bromo-2-isopropoxyphenyl)- 2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (1.87 g, 70% yield).
  • 10MEW79 was prepared from 6-fluoro-3-(2-isopropoxyphenyl)- 2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one using a general acyl chloride addition procedure (0.296 mg, 69% yield).
  • 8MEW98 was prepared from 3-(2-isopropoxyphenyl)-6,7- dimethoxy-2-(piperazin-1 -ylmethyl)quinazolin-4(3H)-one using the general acyl chloride addition procedure (54 mg, 53% yield).
  • 1 H NMR 300 MHz, chloroform-d
  • ⁇ 7.64 p.p.m. (s, 1 H), 7.50 ? 7.39 (m, 1 H), 7.28 ? 7.16 (m, 5H), 7.13-7.02 (m, 2H), 6.92 ?
  • NMR spectra were obtained on a Bruker DPX 300 or 400 MHz spectrometer. CI-MS spectra were taken on a Nermag R-10-10 instrument.
  • the starting material, picolinic acid 1 was first converted to the 4-chloropyridine-2-carbonyl chloride hydrochloride 2 in 90% yield using thionyl chloride and a catalytic amount of dimethylformamide (DMF). Amidation of the acid chloride 2 with methylamine and dimethylamine in the presence of triethylamine as an HCI acceptor gave the amides 3a and 3b in 94% and 90% yield, respectively.
  • the chloroamides 3a and 3b were coupled with 4-aminophenol to give the ethers 4a (also called "CA-1 ”) and 4b in 70% and 69% yield, respectively.
  • the ether side chains were introduced using potassium terf-butoxide in the presence of potassium carbonate. These conditions allowed a chemo-selective ArSN2 addition of the phenoxide; therefore, the main product was the ether, not the secondary amine. Finally, urea bond formation was performed at room temperature, in dichloromethane, between the aniline of the ethers 4a and 4b and the 4-chloro-3- (fluoromethyl)phenyl isocyanate 5. The final sorafenib products 4a and 4b were isolated in 90% and 92% yield, respectively.
  • the crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to provide the 4-(4-(3,5-bis-(trifluoromethyl)- phenylamidophenoxy)-/V-methylpyridine-2-carboxamide (SRS14-95) and 4-(4- (4-chloro-3-(trifluoromethyl)phenylamido)phenoxy)-/V-methylpyridin carboxamide (SRS15-11 ), respectively.
  • the crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to provide the 4-(4-(3,5- bis(trifluoromethyl)phenylsulfonamido)-phenoxy)-/V-methylpyridine-2- carboxamide (SRS14-96) and 4-(4-(4-chloro-3-(trifluoromethyl)- phenylsulfonamido)phenoxy)-/ ⁇ /-methylpyridine-2-carboxamide (SRS14-97) respectively.
  • Sorafenib, regorafenib, imatinib and nilotenib were from SelleckChem (Houston, USA). The synthesis of sorafenib and sorafenib analogs is as set forth above. Unless otherwise indicated, all other compounds were from Sigma-Aldrich (St. Louis, USA).
  • BJeHLT and BJeLR cells were obtained from Robert Weinberg (Whitehead Institute, Cambridge, MA). BJeHLT cells express human telomerase (hTERT), large T antigen (LT) and small T antigen (ST); BJeLR cells express hTERT, LT, ST and an oncogenic HRAS allele (HRAS V12 ). SV40-transformed MEFs were obtained from Craig Thompson (Memorial Sloan Kettering, New York, NY). 143B cells were obtained from Eric Schon (Columbia Medical School, New York, NY). HT-1080 and Calu-1 cells were obtained from American Type Culture Collection.
  • BJeHLT and BJeLR cells were grown in DMEM High-Glucose media (Gibco/Life Technologies Corp., Carlsbad, CA) plus 20% M199 (Sigma) and 15% heat-inactivated fetal bovine serum (FBS).
  • HT-1080 cells were grown in DMEM High-Glucose media (Gibco) supplemented with 10% FBS and 1 % non-essential amino acids (Gibco).
  • Calu-1 and U2OS cells were grown in McCoy's 5A media (Gibco) supplemented with 10% fetal bovine serum.
  • MEFs were grown in DMEM supplemented with 10% fetal calf serum.
  • 143B cells were grown in DMEM High-Glucose supplemented with 10% FBS. All cell lines were grown in humidified tissue culture incubators (Thermo Scientific, West Palm Beach, FL) at 37°C with 5% CO 2 . Except where indicated, all medias were supplemented with penicillin and streptomycin (Gibco).
  • Multicellular tumor spheroids were grown in 96-well Corningware Ultra Low Attachment (ULA) Plates (CLS 3474). 200 ⁇ of cell suspension containing 10 4 cells/ml were added to each well of the ULA plate, after which they were incubated at 37°C/5% CO 2 for 72 hours to allow for MCTS formation.
  • MCTSs were then treated with lethal compounds (vehicle control [DMSO], 10 ⁇ Erastin, 1 ⁇ RSL3, or 1 ⁇ STS) +/- inhibitors (vehicle control [DMSO], 1 ⁇ Ferrostatin-1 , or 25 ⁇ ⁇ -mercaptoethanol) by carefully aspirating 50 ⁇ _ of media from each well, and replacing with 50 ⁇ _ each of media containing 4x desired treatment concentration of the lethal or inhibitor.
  • MCTS images were acquired using an EVOS fl microscope (Advanced Microscopy Group/Life Technologies Corp.) equipped with a 10x phase contrast objective. Three independent fields were acquired for each experimental condition. Viability was then measured using Alamar blue as described above and measured on a Victor3 plate reader.
  • 200,000 HT-1080 or Calu-1 cells/well were seeded overnight in 6-well dishes (Corning Life Sciences, Tewksbury, USA). The next day, cells were washed twice in pre-warmed Na + -free uptake buffer (137 mM choline chloride, 3 mM KCI, 1 mM CaCI 2 , 1 mM MgCI 2 , 5 mM D-glucose, 0.7 mM K 2 HPO 4 , 10 mM HEPES, pH 7.4), then incubated for 10 minutes at 37°C in 1 ml_ of uptake buffer, to deplete cellular amino acids.
  • pre-warmed Na + -free uptake buffer 137 mM choline chloride, 3 mM KCI, 1 mM CaCI 2 , 1 mM MgCI 2 , 5 mM D-glucose, 0.7 mM K 2 HPO 4 , 10 mM HEPES, pH 7.4
  • 50 ⁇ _ of medium per well was removed and transferred to a 96-well assay plate (Corning) and incubated with 50 ⁇ _ of a reaction mixture containing glutamate oxidase, L- alanine, glutamate-pyruvate transaminase, horseradish peroxidase and Amplex Red reagents as per the manufacturers protocol.
  • Glutamate release was first normalized to total cell number determined by Vi-Cell counting at the end of the experiment, then values were expressed as a percentage of no treatment (DMSO) controls. In some experiments, a glutamate standard curve was used to quantify the exact amount of glutamate release.
  • the total amount of glutamate release reflects the activity of both system x c " (Na + -independent) and non-system x c " glutamate transporters and, therefore, never reaches 100% inhibition as system x c ⁇ accounts for only a portion of the total glutamate release.
  • HT-1080 cells were reverse transfected with siRNAs (Qiagen, Germantown, USA) using Lipofectamine RNAiMAX (LFMax, Invitrogen/Life Technologies Corp.). Briefly, 1 -10 nM (final concentration) of siRNAs were aliquoted into 250 ⁇ _ Opti-MEM media (Gibco) in the bottom of each well of a 6-well dish (Corning). An additional 250 ⁇ _ media + LFMax was added to each well and incubated for 15 minutes. At this point, 150,000 HT-1080 cells were added to each well in regular HT-1080 media. The plates were swirled to mix and incubated for 48 hours at 37°C in a tissue culture incubator prior to analysis.
  • siRNAs Qiagen, Germantown, USA
  • LFMax Lipofectamine RNAiMAX
  • RT-gPCR Reverse transcription-quantitative polymerase chain reaction
  • RNA samples were used as input for each reverse transcription reaction, performed using the TaqMan RT kit (Applied Biosystems/Life Technologies Corp.). Primer pairs for were designed for target transcripts using Primer Express 2.0 (Applied Biosystems). Quantitative PCR reactions were performed using the Power SYBR Green PCR Master Mix (Applied Biosystems). Triplicate samples per condition were analyzed on an Applied Biosystems StepOnePlus qPCR instrument using absolute quantification settings. Differences in mRNA levels compared to ACTB internal reference control were computed between control and experimental conditions using the AACt method.
  • GSH+GSSG Total intracellular glutathione
  • a glutathione assay kit (Cayman Chemical #703002, Ann Arbor, USA) exactly according to instructions.
  • 200,000 HT-1080 cells per well were seeded overnight in 6-well dishes (Corning). The next day cells were treated with compounds for 5 hours, then washed once in 500 ⁇ _ PBS and harvested by scraping into phosphate buffer (10 mM X, 1 mM EGTA). Cells were then lysed by sonication (7 cycles, 2 sec on, 1 sec off) and spun at 4°C for 15 minutes at 13,000 rpm to pellet membranes.
  • Modulatory effect (M e ) profiling was performed as described (Dixon et al., 2012).
  • the following ferroptosis inhibitors were tested (high dose of 10 point, 2-fold dilution series in brackets): cycloheximide (CHX, 50 ⁇ ), ferrostatin-1 (Fer-1 , 2 ⁇ ), trolox (300 ⁇ ), U0126 (15 ⁇ ), ciclopirox olamine (CPX, 50 ⁇ ) and beta-mercaptoethanol ( ⁇ - ⁇ , 20 ⁇ ).
  • Cells were seeded at 1500 cells/well in a volume of 40 ⁇ _ media in 384 well plates (Corning) for 24 hours prior to treatment of lethals and/or inhibitors. Following compound treatment for 24 hours, 10 ⁇ _ of a 1 :100 v/v dilution of Apo-One Homogeneous Caspase 3/7 substrate solution/assay buffer (Promega, Madison, USA) was added to samples and the plate was vigorously agitated for 30 seconds.
  • Apo-One Homogeneous Caspase 3/7 substrate solution/assay buffer Promega, Madison, USA
  • FAERS Adverse Event Reporting System
  • FAERS Adverse Event Reporting System
  • EHR electronic health records
  • ferroptotic death phenotype whether induced by erastin or SAS, appears to be indistinguishable in all cell lines tested, and in all cases involves inhibition of system x c " function, as suggested by the consistent suppression of death by ⁇ - ⁇ .
  • Example 4 Inhibition of system x g " causes depletion of glutathione, which is necessary for erastin-induced ferroptosis
  • cystine Within cells cystine is reduced to cysteine (Bannai and Ishii, 1982), which serves as the rate-limiting precursor for the synthesis of the tripeptide glutathione ( ⁇ -L-glutamyl-L-cysteinylglycine), a key intracellular antioxidant (Lushchak, 2012).
  • ⁇ -L-glutamyl-L-cysteinylglycine a key intracellular antioxidant
  • BSO L-buthionine sulfoximine
  • ⁇ -GCS ⁇ - glutamylcysteine synthetase
  • Erastin's quinazolinone core (Region A, Figure 4) is found in a number of biologically active compounds and is considered to be a "privileged" scaffold (Welsch et al., 2010). Modifications to this region (4-10), including substitution of the quinazolinone for quinolone (4) or indole (5), obtained using a Meth-Cohn quinoline synthesis, all resulted in moderate to severe losses of lethal potency compared to 3, suggesting that the unmodified quinazolinone scaffold is essential for the lethality of erastin.
  • RNA sequencing RNA sequencing (RNA-Seq) of mRNA from HT-1080 cells treated for 5 hours with DMSO, erastin (10 ⁇ ), ⁇ - ⁇ (18 ⁇ ) or erastin + ⁇ - ⁇ .
  • PD markers can be used to determine when cells are responding to system x c " inhibition, such as in response to erastin. This will be crucial for the further clinical development of such agents, to determine effective exposure of tissues in vivo.
  • CHAC1 ⁇ 24-fold, Figure 5A.
  • RT-qPCR erastin induced up-regulation of CHAC1 in both HT-1080 and Calu-1 cells, as well as in erastin-sensitive mouse embryonic fibroblasts ( Figure 5C, Figure 5F), validating the results of the RNA-Seq analysis.
  • CHAC1 is an ER-stress-responsive gene upregulated downstream of the canonical ATF4-ATF3-CHOP ER stress response pathway (Gargalovic et al., 2006, Mungrue et al., 2009). Indeed, CHAC1 upregulation was observed in response to the ER stress-inducing agent thapsigargin ( Figure 5F), and a number of the genes identified by RNA-seq to be up- regulated by erastin are known regulators of the ER stress response (e.g. ATF3, DDIT3 (CHOP)).
  • CHAC1 up-regulation was observed in response to a 5 hour treatment with erastin, SAS and sorafenib (see below), but not in response to: (i) other iron-dependent, oxidative lethal agents (RSL3, artesunate), (ii) rotenone, an agent that triggers mitochondrial ROS production (Barrientos and Moraes, 1999, Dixon et al., 2012), or (iii) a 30 hour treatment with the glutathione-depleting agent BSO ( Figure 5D; Figure 5G).
  • RSL3 iron-dependent, oxidative lethal agents
  • rotenone an agent that triggers mitochondrial ROS production
  • a 30 hour treatment with the glutathione-depleting agent BSO Figure 5D; Figure 5G
  • Modulatory profiling identifies sorafenib as an inhibitor of system x g - "
  • sorafenib like RSL3 and PAO, could impact a glutathione-dependent process essential for cell viability.
  • sorafenib like RSL3 and PAO, could impact a glutathione-dependent process essential for cell viability.
  • sorafenib (10 ⁇ , 24 hours), like the positive control erastin (10 ⁇ , 24 hour), induced cell death that was significantly inhibited by co-treatment with ⁇ - ⁇ , Fer-1 and DFO, consistent with induction of ferroptosis (Figure 6C).
  • STS non-specific kinase inhibitor staurosporine
  • the ability of ⁇ - ⁇ to prevent sorafenib-induced cell death implied that sorafenib, like erastin and SAS (but unlike RSL3) triggers ferroptosis by inhibiting system x c " .
  • sorafenib but not the ABL kinase inhibitor imatinib, caused a dose-dependent inhibition of system x c " -mediated glutamate release in HT- 1080 cells (Figure 6D).
  • the ability of sorafenib and erastin to suppress system x c " activity was not inhibited by co-treatment with Fer-1 , demonstrating that this effect is up-stream of Fer-1 -sensitive ROS accumulation (Figure 6D).
  • sorafenib activates an ER stress response by depriving cells of cysteine.
  • sorafenib can trigger ferroptosis and does so by inhibiting system x c " activity and blocking the uptake of cystine.
  • Sorafenib could conceivably inhibit system x c " activity by modulating the activity of kinases that control system x c " function, through modulation of a novel target (e.g. SLC7A1 1 itself, or a related regulatory protein) or through both mechanisms acting in parallel.
  • a novel target e.g. SLC7A1 1 itself, or a related regulatory protein
  • the scaffold into three regions of interest: the anilino aryl ring, the urea and the phenoxypyridinecarboxamide (red, blue and green, respectively, in Figure 7A).
  • analogs with only a phenyl ring (24) or lacking the CF 3 group (25) were inactive at the highest concentrations tested in our assay (EC50 > 40 ⁇ ), indicating that the CF 3 group is essential for the induction of ferroptosis.
  • sorafenib analogs were evaluated for their effects on system x c " function, using the glutamate release assay, and on caspase- 3/7 activity, using a fluorogenic substrate cleavage assay. Consistent with the above data, two active (e.g. lethal) sorafenib analogs (SRS13-45 (28) and SRS13-60 (30)) significantly inhibited system x c " function, while two non-lethal analogs (EC 50 > 40 ⁇ ), SRS13-67 (29) and SRS14-98 (31 ), did not ( Figure 7B).
  • Sorafenib is a clinically-approved drug used to treat renal cell carcinoma and other indications. We knew whether the effects of sorafenib on system x c " uncovered here would result in a unique spectrum of clinical observations in patients treated with sorafenib. Previously, we applied a large-scale statistical analysis to the Food and Drug Administration Adverse Event Reporting System (FAERS) to systematically identify drug effects and interactions (Tatonetti et al., 2012). Here, we sought to use this approach to discover correlations between sorafenib exposure and human health unique to this drug.
  • FAERS Food and Drug Administration Adverse Event Reporting System
  • sorafenib Focusing on sorafenib, we observed that, compared to other clinically approved kinase inhibitors, none of which are known (e.g. imatinib, Figure 6D) or likely to inhibit system x c " , sorafenib has a unique adverse event profile. Most notably, sorafenib treatment was associated with a significant number of adverse events in 15/20 physiological system categories, the most observed in this analysis for any drug. Conversely, imatinib was associated with a significant number of adverse events in 0/20 categories.
  • CHAC1 up-regulation may be useful as a transcriptional biomarker for cells undergoing cystine limitation. What role CHAC1 plays in the cell or in ferroptosis remains unclear. ChaC- family proteins were recently reported to function as intracellular reduced glutathione (GSH)-degrading enzymes in yeast (Kumar et al., 2012).
  • sorafenib set forth herein indicates that, at least in certain cases, the elimination of features crucial for high affinity sorafenib-RAF interaction have only modest effects on the ability of these compounds to induce ferroptosis, suggesting that it may be possible to dissociate the kinase-binding and system x c " -inhibitory activity of this scaffold.
  • sorafenib inhibits system x c " and triggers the amino acid deprivation response (as indicated by up-regulation of CHAC1) provides a mechanistic explanation for previous observations that sorafenib treatment inhibits translation (Rahmani et al., 2005), induces ER stress (Rahmani et al., 2007) and enhances sensitivity to ROS (Shiota et al., 2010).
  • DMSO % Gl means growth inhibition compared to DMSO control.
  • B-ME % Gl mean growth inhibition compared to ⁇ -mercaptoethanol.
  • Fer-1 % Gl means growth inhibition compared to Ferrostatin-1 .
  • SD refers to suppression of death. All reported values are from 10 ⁇ treatments.

Abstract

La présente invention concerne,entre autre, des composés représentés par la formule I; l'invention concerne également des compositions pharmaceutiques et des kits contenant de tels composés. L'invention concerne également des méthodes d'utilisation de tels composés et de telles compositions ainsi que des trousses pour traiter un sujet souffrant d'un dérèglement du système xc- , pour activer la ferroptose, pour inhiber le système xc- dans une cellule et pour surveiller le traitement d'un sujet souffrant d'un dérèglement du système xc- .
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JP7129085B2 (ja) 2016-05-30 2022-09-01 テクニッシュ ウニヴェルジテート ミュンヘン 抗菌薬物としてのウレアモチーフ含有化合物およびその誘導体
JP2019524644A (ja) * 2016-05-30 2019-09-05 テクニッシュ ウニヴェルジテート ミュンヘン 抗菌薬物としてのウレアモチーフ含有化合物およびその誘導体
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JP2019528279A (ja) * 2016-08-17 2019-10-10 アイカーン スクール オブ メディシン アット マウント サイナイ キナーゼ阻害物質化合物、組成物、及びがんの治療方法
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WO2018035346A1 (fr) * 2016-08-17 2018-02-22 Ichan School Of Medicine At Mount Sinal Composés inhibiteurs de kinase, compositions et méthodes de traitement du cancer
WO2018218087A1 (fr) * 2017-05-24 2018-11-29 K-Gen, Inc. Méthodes de traitement du cancer
WO2019071353A1 (fr) * 2017-10-13 2019-04-18 Exerkine Corporation Utilisation d'inhibiteur du système xc- pour le traitement de la myalgie induite par la statine
US11098040B2 (en) 2018-02-28 2021-08-24 Ferro Therapeutics, Inc. Compounds and methods of use
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US11040964B2 (en) 2019-02-27 2021-06-22 Ferro Therapeutics, Inc. Compounds and methods of use
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WO2021030783A1 (fr) * 2019-08-15 2021-02-18 Duke University Compositions et procédés pour le traitement du cancer et de troubles du snc
WO2021050490A1 (fr) * 2019-09-13 2021-03-18 The Trustees Of Columbia University In The City Of New York Procédés d'amélioration de la radiothérapie au moyen d'inducteurs de ferroptose en tant que radiosensibilisateurs
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