WO2017193086A1 - Composés et méthodes thérapeutiques - Google Patents

Composés et méthodes thérapeutiques Download PDF

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Publication number
WO2017193086A1
WO2017193086A1 PCT/US2017/031427 US2017031427W WO2017193086A1 WO 2017193086 A1 WO2017193086 A1 WO 2017193086A1 US 2017031427 W US2017031427 W US 2017031427W WO 2017193086 A1 WO2017193086 A1 WO 2017193086A1
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cancer
rxra
cells
inhibitor
tnfa
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PCT/US2017/031427
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English (en)
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Kanyin E. Zhang
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Tarrex Biopharma Inc.
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Publication of WO2017193086A1 publication Critical patent/WO2017193086A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/62—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings and other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton

Definitions

  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a truncated-RXRa antagonist, wherein the truncated- RXRa antagonist induces apoptosis in a portion of the cancer cells.
  • Another embodiment provides the method wherein the cancer cells have increased TNFa levels compared to the equivalent non-cancer cells.
  • Another embodiment provides the method further comprising coadministration of TNFa.
  • Another embodiment provides the method wherein the portion of cancer cells in which apoptosis is induced is greater than the portion of apoptotic cancer cells induced by the administration of the truncated-RXRa antagonist alone.
  • Another embodiment provides the method wherein the portion of cancer cells in which apoptosis is induced is greater than the portion of apoptotic cancer cells induced by the administration of the truncated-RXRa antagonist alone. Another embodiment provides the method wherein the portion of cancer cells in which apoptosis is induced is greater than the portion of apoptotic cancer cells induced by the administration of the truncated-RXRa antagonist and TNFa alone. Another embodiment provides the method wherein the cancer cells are colorectal cancer cells. Another embodiment provides the method wherein the colorectal cancer cells harbor KRAS mutation. Another embodiment provides the method wherein the colorectal cells are resistant to cetuximab.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a truncated-RXRa antagonist. Another embodiment provides the method wherein the truncated-RXRa antagonist lacks COX-1 or COX-2 activities. Another embodiment provides the method wherein the truncated-RXRa antagonist is free of COX-1 or COX-2 activities. Another embodiment provides the method wherein the truncated- RXRa antagonist is substantially free of COX-1 or COX-2 activities. Another embodiment provides the method wherein the truncated-RXRa antagonist has a COX-1 and COX-2 IC 50 greater than 1000 ⁇ . Another embodiment provides the method wherein the truncated-RXRa antagonist is TX803, or a pharmaceutically acceptable salt thereof.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a truncated-RXRa antagonist and an inhibitor of the Ras-Raf-Mek-Erk Kinase pathway selected from a MEK inhibitor, a RAF inhibitor, or an Erk 1/2 inhibitor.
  • Another embodiment provides the method wherein the inhibitor of the Ras-Raf- Mek-Erk Kinase pathway is a MEK inhibitor.
  • Another embodiment provides the method wherein the MEK inhibitor is cobimetinib.
  • Another embodiment provides the method wherein the MEK inhibitor is trametinib.
  • Another embodiment provides the method wherein the inhibitor of the Ras-Raf-Mek-Erk Kinase pathway is a RAF inhibitor.
  • RAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib (formerly LGX818), PLX-4720, sorafenib, TAK-632, MLN2480, SB90885, XL281, RAF265, or any combination thereof.
  • the inhibitor of the Ras-Raf-Mek-Erk Kinase pathway is an Erk 1/2 inhibitor.
  • Erk 1/2 inhibitor is selected from SCH772984, VTXl le, BIX02189, ERK5- IN-1, FR180204, Pluripotin, TCS ERK l ie, XMD 8-92, DEL-22379, or any combination thereof.
  • Figure 1 A illustrates FACS analysis of SW620 cells sorted based on Annexin V-FITC (apoptotic marker, x-axis) and propidium iodide (DNA content and cell viability marker, y-axis) after the indicated treatment (control, Cobimetinib, TX803, and TX803 and Cobimetinib(Cobi)) with and without TNFa (T);
  • Annexin V-FITC apoptotic marker, x-axis
  • propidium iodide DNA content and cell viability marker, y-axis
  • Figure IB illustrates a graph of percentage of apoptosis of SW620 cell line treated with
  • FIG. 2A illustrates FACS analysis of HCT116 cells sorted based on Annexin V-FITC
  • Figure 2B illustrates a graph of percentage of apoptosis of HCT116 cell line treated with Cobimetinib (1 ⁇ ), TX803 (5 ⁇ ), and a combination of Cobimetinib (Cobi) (1 ⁇ ) and TX803 (5 ⁇ ) with and without TNFa (25 ng/mL);
  • Figure 3 illustrates a graph of percentage of survival in SW620 cells treated with Cobimetinib (Cobi) or a combination of Cobimetinib (Cobi) and TX803 for the indicated concentrations
  • Figure 4 illustrates a graph of percentage of survival in SW620 cells treated with Cobimetinib (Cobi) or a combination of Cobimetinib (Cobi) and TX803 with and without TNFa;
  • Figure 5 illustrates a graph of percentage of survival in HCT116 cells treated with Cobimetinib (Cobi) or a combination of Cobimetinib (Cobi) and TX803 for the indicated concentrations
  • Figure 6 illustrates a graph of percentage of survival in HCT116 cells treated with Cobimetinib (Cobi) or a combination of Cobimetinib (Cobi) and TX803 with and without TNFa;
  • Figure 7A illustrates SW620 mice after treatment with a negative control, positive control, or TX803 respectively and the extracted tumors from each;
  • Figure 7B illustrates the average weight of tumors extracted from SW620 mice as depicted in Figure 7A;
  • Figure 8 illustrates Western blots indicating presence of full-length (FL) or truncated (t) RXRa in the indicated tissue types from colon cancer patients or rectal cancer patients;
  • Figure 9A illustrates Western blots of TX803 treatment (0, 2.5, 5, 10, 20, and 40 uM) and measuring apoptosis in SW620 cells by detecting PARP and cleaved PARP.
  • ⁇ -actin is used as a loading control;
  • Figure 9B illustrates Western blots of TX803 treatment (0, 1.25, 2.5, 5, 10, and 20 uM) and measuring apoptosis in HCT116 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 9C illustrates Western blots of TX803 treatment (0, 2.5, 5, 10, and 20 uM) and measuring apoptosis in H292 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 9D illustrates Western blots of TX803 treatment (0, 2.5, 5, 10, and 20 uM) and measuring apoptosis in MCF-7 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 9E illustrates Western blots of TX803 treatment (0, 2.5, 5, 10, and 20 uM) and measuring apoptosis in MDA-MB-231 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • FIG 10A illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in SW620 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 10B illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in HCT116 cells by detecting PARP and cleaved PARP;
  • Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure IOC illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in HT-29 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 10D illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in HepG2 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 10E illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in H292 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • Figure 10F illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in A549 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • FIG. 10G illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in MCF-7 cells by detecting PARP and cleaved PARP.
  • ⁇ -actin is used as a loading control;
  • Figure 10H illustrates Western blots of control (C), TNFa (T), TX803, and TX803 and TNFa (T) treatment measuring apoptosis in MDA-MB-231 cells by detecting PARP and cleaved PARP. Truncated (t) RXRa and RXRa are also detected, ⁇ -actin is used as a loading control;
  • TX803 (30 mg/kg daily for two weeks), Cobimetinib (10 mg/kg daily for two weeks), or Cobimetinib and TX803 (TX803 15 mg/kg plus Cobimetinib 5 mg/kg daily for two weeks).
  • Body weight in grams (g) is shown on a Y-axis;
  • Figure 12A is a Western blot analysis of control, TX803, Cobimetinib, and Cobimetinib and TX803 detecting RXR-A197, p-ERK, and PARP.
  • ⁇ -actin is used as a loading control;
  • Figure 13 is a plot of tumor volume in a PDX colon cancer mouse model in mice treated with control, TX803, and Cobimetinib (Cobi) and TX803.
  • Tumor volume (mm 3 ) is plotted on a Y- axis versus days on a X-axis; and
  • Figure 14 is a plot of body weight in a PDX colon cancer mouse model in mice treated with control, TX803, and Cobimetinib (Cobi) and TX803.
  • Body weight (g) is plotted on a Y-axis versus days on a X-axis.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of TX803 described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of TX803 are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine,
  • treatment or “treating” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • Retinoid X Receptors are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • Retinoid X Receptors are type II nuclear receptors that mediate biological effects of retinoids. RXRs are activated by retinoic acid and subsequently activate specific target gene expression. There are three RXRs, RXRa, - ⁇ , and - ⁇ . RXRs mediate retinoic acid-mediated gene activation through homodimerization, or heterodimerization with subfamily 1 nuclear receptors including CAR, FXR, LXR, PPAR, PXR, TR, and VDR.
  • Retinoid X receptor a also known as R2B1 (nuclear receptor subfamily 2, group B, member 1), is a ligand-dependent transcription factor that regulates a wide range of biological functions, including cell differentiation, growth, and apoptosis (Germain et al., 2006; Szanto et al., 2004).
  • RXRa resides in the cytoplasm at certain stages during development (Dufour and Kim, 1999; Fukunaka et al., 2001) and migrates from the nucleus to the cytoplasm in response to differentiation, apoptosis, and inflammation (Cao et al., 2004; Casas et al., 2003; Zimmerman et al., 2006).
  • RXRa exhibits a modular organization structurally consisting of three main functional domains: an N-terminal region, a DNA-binding domain and a ligand-binding domain (LBD).
  • LBD possesses a ligand-binding pocket (LBP) for the binding of small molecule ligands, a transactivation function domain termed AF-2 composed of Helix 12 (HI2) of the LBD, a coregulator binding surface, and a dimerization surface (Germain et al., 2006; Szanto et al., 2004).
  • LBP ligand-binding pocket
  • RXRa Upon agonist binding, RXRa dissociates from the corepressor and recruits a coactivator protein, which subsequently promotes transcription of downstream target genes.
  • Agonist ligand binds to the LBP and helps the H12 to adopt the active conformation that forms a surface to facilitate the binding of coactivators and subsequent transactivation.
  • the H12 adopt an inactive conformation that favors the binding of corepressors to inhibit target gene transcription.
  • Such inactivation of RXRa can induce histone deacetylation, chromatin condensation, and transcriptional suppression.
  • RXRa Due to its role in many regulatory processes, RXRa is an attractive molecular target for drug development. Natural RXRa ligand 9-cis-retinoic acid (9-cis-RA) and synthetic ligands have been effective in preventing tumorigenesis in animals and RXRa has been a drug target for therapeutic applications, especially in the treatment of cancer (Bushue and Wan, 2010; Yen and Lamph, 2006; Altucci and Gronemeyer, 2001; Dawson and Zhang, 2002). 9-cis-retinoic acid (9- cis-RA), several polyunsaturated fatty acids, and the NSAID Etodolac (Kolluri et al., 2005) can bind to RXRa to regulate different biological functions. Targretin, a synthetic RXR ligand, is currently used for treating cutaneous T-cell lymphoma (Dawson and Zhang, 2002),
  • RXRa for cancer therapy. Consistently, the oncogenic potential of RXRa has been demonstrated. Genetic disruption of RXRa enhances tumorigenesis (Huang et al., 2002; Li et al., 2001), and RXR binding to PML/RAR is essential for the development of acute promeylocytic leukemia (Zeisig et al., 2007; Zhu et al., 2007). However, inhibitors designed to target full-length RXRa can be toxic to other non-cancerous cells.
  • RXRa is cut at the N-terminus.
  • the resulting truncated RXRa migrates from the nucleus and recruits PI3K to the cell membrane through its interaction with p85a. This recruiting of PI3K leads to its activation, by receptors such as TNFR1, and initiation of the PI3K/AKT survival pathway. Therefore, tRXRa, unlike full-length RXRa, activates cell survival pathways in cancer cells (Zhou et al., 2010, Cancer Cell 17:560-573).
  • tRXRa is often produced in tumor tissues but not in normal tissues.
  • RXRa is cleaved in tumor but not in premalignant or normal tissues from patients with prostate or thyroid cancer (Takiyama et al., 2004; Zhong et al., 2003).
  • agents targeting tRXRa- mediated pathway can be effective and tumor specific.
  • AKT has been shown to be overexpressed in many cancers, including colon, pancreatic, ovarian, and some breast cancers (Roy et al., 2002, Carcinogenesis 23 :201-205; Asano et al., 2004, Oncogene 23 :8571-8580). Phosphorylated, and thereby activated, AKT delivers survival signal (Datta et al., 1997, Cell 91 :231-241). Conversely, inhibition of AKT signaling can lead to induction of apoptosis in some cancers (Yuan et al., 2000, Oncogene 19:2324-2330; Page et al., Int J Oncol 17:23-28).
  • the tRXRa antagonist is TX803, or a pharmaceutically acceptable salt thereof.
  • TX803 lacks COX-1 and COX-2 inhibitory activities (IC 50 >1000 ⁇ for both), and thereby mitigates the potential for gastrointestinal and cardiotoxicities which are associated with NSAIDs.
  • the synthesis and characterization of TX803 is provided in WO 2011/140525 or US 9,611,235.
  • TX803 is also known as (Z)-2-(5-fluoro-l-(4-isopropylbenzylidene)-2-methyl-lH-inden-3- yl)acetic acid and has the chemical structure shown below.
  • tRXRa such as TX803 or a pharmaceutically acceptable salt thereof
  • binding of TX803 to tRXRa dissociates it from PI3K.
  • Dissociation of PI3K from tRXRa turns off the erroneous PI3K/AKT mediated cell survival pathway.
  • tRXRa such as TX803 or a pharmaceutically acceptable salt thereof
  • methods for using antagonists of tRXRa such as TX803 or a pharmaceutically acceptable salt thereof, in combination with other therapeutic agents.
  • methods of synergistically inhibiting tRXRa-dependent AKT activation with TX803 and T Fa are disclosed herein.
  • TX803 -tRXRa binding converts the cytokine TNFa from a cancer cell survival factor to a cancer cell killer via apoptosis.
  • TNFa plays important roles in diverse cellular events such as cell survival and death. However, it often fails to induce apoptosis in cancer cells due to its simultaneous activation of the NF- ⁇ and/or the PI3K/AKT pathway (Aggarwal, 2003; Balkwill, 2009).
  • TNFa is elevated in tumor environments, including following immuno-therapy.
  • Retinoids in combination with cytokines can synergistically induce differentiation or apoptosis of human transformed cells (Altucci et al., 2005) whereas combination of retinoids and TNFa can overcome retinoic acid resistance in some cancers (Witcher et al., 2004).
  • cytokines such as TNFa and TNF-related apoptosis inducing ligand (TRAIL)
  • TRAIL TNF-related apoptosis inducing ligand
  • the MAPK/ERK pathway is also commonly up- regulated in cancer cells.
  • the MAPK pathway is initiated by a ligand binding to a receptor, such as EGFR, and culminates with transcription activation or repression of target genes. In many cancers, the MAPK pathway is stuck in the on position. Inhibitors of MAPK pathway components, such as MEK inhibitors, can reverse this mis-activation.
  • MEK inhibitors include, for example, trametinib (GSK1120212), cobimetinib, XL518, binimetinib, selumetinib, PD- 325901, CI-1040, PD035901, and TAK-733 (Wang et al, 2007, Biochem Biophys Acta
  • Additional MEK inhibitors include MEK162, AZD6244, R05126766, and GDC-0623.
  • MEK is activated by a RAF protein kinase, such as BRAF, CRAF, or ARAF.
  • BRAF inhibitors include vemurafenib, dabrafenib, encorafenib (formerly LGX818), PLX-4720.
  • Other RAF inhibitors include sorafenib, TAK-632, MLN2480, SB90885, XL281, and RAF265.
  • ERK ERK1 and/or ERK2
  • mitogen-activated protein kinase MAPK
  • Inhibitors of ERK include SCH772984, VTXl le, BIX02189, ERK5-IN-1, FR180204, Pluripotin, TCS ERK l ie, XMD 8-92, and DEL-22379.
  • tRXRa antagonists Disclosed herein are tRXRa antagonists.
  • the tRXRa antagonist is TX803 or a pharmaceutically acceptable salt thereof.
  • the tRXRa antagonist lacks COX-1 and/or COX-2 inhibitory activities.
  • tRXRa antagonists such as TX803 or a pharmaceutically acceptable salt thereof, to block TNFa-induced AKT-mediated survival function. Since TNFa can induce both apoptosis and cell survival, by blocking the cell survival pathway, T Fa function in cancerous cells shifts from initiating cell survival to initiating cell death.
  • tRXRa antagonists such as TX803 or a pharmaceutically acceptable salt thereof, which results in a two-fold therapeutic effect:
  • tRXRa antagonists as disclosed herein, turn off cell survival pathways and turn on apoptosis pathways in targeted cancerous cells.
  • tRXRa antagonists and MEK inhibitors.
  • TNFa is also co-administered.
  • methods disclosed herein comprise administration of tRXRa antagonists.
  • the antagonist comprises TX803 or a pharmaceutically acceptable salt thereof.
  • methods disclosed herein comprise administration of tRXRa antagonists in combination with other agents.
  • other agents comprise TNFa.
  • TNFa is endogenously overexpressed in cells in which the treatment is being administered.
  • TNFa is co-administered with a tRXRa antagonist, such as TX803 or a pharmaceutically acceptable salt thereof.
  • methods disclosed herein comprise administration of tRXRa antagonists in combination with other agents.
  • the tRXRa antagonist comprises TX803 or a pharmaceutically acceptable salt thereof.
  • the coadministered agent comprises a MEK inhibitor.
  • the MEK inhibitor comprises cobimetinib.
  • the MEK inhibitor comprises trametinib.
  • the MEK inhibitor is selected from trametinib, cobimetinib, XL518, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, TAK-733, MEK162, AZD6244, R05126766, and GDC-0623, or any combination thereof.
  • TNFa is endogenously overexpressed in cells in which the treatment is being administered.
  • TNFa is co-administered with the tRXRa antagonist and MEK inhibitor.
  • the co-administered agent comprises a RAF inhibitor.
  • the RAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib
  • the co-administered agent comprises an Erk 1/2 inhibitor.
  • the Erk 1/2 inhibitor is selected from SCH772984, VTXl le, BIX02189, ERK5-IN-1, FR180204, Pluripotin, TCS ERK l ie, XMD 8-92, DEL-22379, or any combination thereof.
  • the TX803, or a pharmaceutically acceptable salt thereof is administered as a pure chemical.
  • the TX803, or a pharmaceutically acceptable salt thereof is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • composition comprising the TX803, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • the carrier(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising the TX803, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the TX803, or a pharmaceutically acceptable salt thereof is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis byproducts that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • the dose of the composition comprising TX803, or a pharmaceutically acceptable salt thereof differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the
  • composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • Colorectal cancer is one of the most common cancers worldwide (Jemal et al., 2010 Cancer J. Clin. 60:277-300). With the emergence of two anti-epidermal growth factor receptor (EGFR)-targeted antibodies, cetuximab (Erbitux) and panitumumab (Vectibix), the treatment of metastatic CRC has entered into the era of personalized treatment. However, EGFR, the target of these drugs, which is overexpressed in approximately 80% of colorectal
  • KRAS gene is a strong negative predictive biomarker to indicate whether a CRC patient will respond to anti-EGFR treatment.
  • target treatment may also be toxic and expensive, KRAS mutation status detection has become a common diagnostic tool.
  • new and effective therapeutics are needed for the treatment of patients which harbor such KRAS mutation.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising (Z)-2-(5-fluoro-l-(4- isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising cobimetinib, or a pharmaceutically acceptable salt thereof.
  • Another embodiment provides the method wherein the cobimetinib is administered as the fumarate salt.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising (Z)-2- (5-fluoro-l-(4-isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising trametinib, or a pharmaceutically acceptable salt thereof.
  • compositions compri sing (Z)-2-(5 -fluoro- 1 -(4-i sopropylbenzylidene)-2-methyl - 1 H-inden-3 - yl)acetic acid, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprising cobimetinib or trametinib, or pharmaceutically acceptable salts thereof, are provided in separate dosage forms.
  • composition comprising (Z)-2-(5-fluoro-l-(4-isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprising cobimetinib or trametinib, or pharmaceutically acceptable salts thereof, are provided in the same dosage form.
  • composition comprising (Z)-2-(5-fluoro-l-(4-isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a
  • the cancer is selected from colon cancer, rectal cancer, gastric cancer, or breast cancer.
  • method wherein the cancer is selected from colon cancer or breast cancer.
  • Another embodiment provides the method wherein the cancer is selected from gastric cacncer. Another embodiment provides the method wherein the cancer is colon cancer. Another embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method the breast cancer does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu. Another embodiment provides the method wherein the breast cancer does not express the genes for estrogen receptor (ER), or progesterone receptor (PR). Another embodiment provides the method wherein the cancer is characterized by a KRAS mutant.
  • Another embodiment provides the method wherein the cancer is further characterized by expression of tRXRa.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising (Z)-2-(5-fluoro-l-(4- isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a MEK inhibitor.
  • MEK inhibitor is selected from trametinib, cobimetinib, XL518, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, TAK-733, MEK162, AZD6244, R05126766, and GDC-0623, or any combination thereof.
  • cancer is selected from colon cancer, rectal cancer, gastric cancer, or breast cancer.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising (Z)-2-(5-fluoro-l-(4- isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a RAF inhibitor.
  • the RAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib (formerly LGX818), PLX-4720, sorafenib, TAK-632, MLN2480, SB90885, XL281, RAF265, or any combination thereof.
  • the cancer is selected from colon cancer, rectal cancer, gastric cancer, or breast cancer.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising (Z)-2-(5-fluoro-l-(4- isopropylbenzylidene)-2-methyl-lH-inden-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a Erk 1/2 inhibitor.
  • the Erk 1/2 inhibitor is selected from SCH772984, VTXl le, BLX02189, ERK5-IN-1, FR180204, Pluripotin, TCS ERK l ie, XMD 8-92, DEL-22379, or any combination thereof.
  • the cancer is selected from colon cancer, rectal cancer, gastric cancer, or breast cancer.
  • Example 1 Increasing apoptosis in SW620 colorectal cells
  • Colorectal cells of the SW620 cell line were plated from 1000-10000 cells per well in a 96-well plate and incubated for 24 hours.
  • the tRXRa antagonist TX803, the MEK inhibitor Cobimetinib, and/or T Fa were added in the amounts and combinations indicated in Table 1. Where indicated, Cobimetinib was added at 0 hours to a final concentration of 1 uM, TX803 was added at 2 hours to a final concentration of either 3 ⁇ or 5 ⁇ , and TNFa was added at 3 hours to a final concentration of 25 ng/mL. Following the indicated treatment cycle, the cells were incubated at 37 degrees Celsius for 24 hours in a C0 2 incubator.
  • IX annexin-binding buffer was prepared by diluting lmL of 5X annexin binding -buffer with 4 mL of deionized water.
  • Propidium Iodide (PI) was prepared as a 100 ⁇ g/mL working solution by diluting 5 ⁇ _, of the 1 mg/mL PI stock solution in 45 IX annexin-binding buffer.
  • Stained cells were analyzed by flow cytometry, measuring the fluorescence emission at 530 nm and 575 nm (or equivalent) using 488 nm excitation. The counting cell number was 10000 every time.
  • Annexin binds and detects the apoptosis marker phosphatidyl serine located on the cell surface of apoptotic cells.
  • Propidium iodide is a DNA intercalating agent and is used as a marker for DNA content, cell cycle stage, and cell viability.
  • Cell survival was also measured using an MTT assay. Briefly, cells were seeded at a density of 8,000 -10,000 cells per well in 96-well plates in RPMI 1640 or DMEM containing 10% FBS. Cells were replenished with fresh complete medium containing either compound or 0.1% DMSO. After 48 hours of incubation, 15 ⁇ of 5 mg/ml MTT (Thiazolyl Blue Tetrazolium Bromide) was added to each well. One set of wells included MTT but no cells and served as a control. Plates were incubated for 4 hours at 37 °C in a culture hood. Media was then removed and 150 ⁇ of MTT solvent (DMSO) was added. Plates were covered with foil and agitated on an orbital shaker for 10 minutes. Absorbance was read at 490 nm with a reference filter of 490 nm.
  • MTT MTT solvent
  • SW620 colorectal cancer model mice were treated with the truncated RXRa antagonist TX803, a positive control molecule, or negative control.
  • the positive control mice and TX803 treated mice were injected with 60 mg/kg of the respective therapeutic intraperitoneally (IP), every other day (Q2D).
  • IP intraperitoneally
  • Q2D the respective therapeutic intraperitoneally
  • mice were measured at the end of the study, the tumor size and weight were measured ( Figures 7A and 7B). Mice treated with TX803 had reduced tumor size compared to both the positive and negative control mice.
  • Example 3 Treatment of colorectal patients with TX803
  • Truncated-RXRa is elevated in tumor tissues from colorectal cancer patients ( Figure 8). Elevated truncated -RXRa levels indicates misregulation of cell survival pathways, such as the PI3K/AKT pathway. Such patients can be treated with TX803 in combination with TNFa in order to turn off the cell survival pathway and turn on apoptosis, as was described and shown in vitro in Example 1.
  • the colorectal cancer patients described above can also be treated with a combination of TX803, TNFa, and the MEK inhibitor Cobimetinib.
  • the MEK inhibitor will turn off the MAPK pathway, which is often also misregulated in colon cancer cells.
  • This combination therapy can lead to a synergistic effect of apoptosis induction greater than any of the three therapeutic agents individually, as was demonstrated in vitro in Example 1.
  • Example 4 Growth inhibition and induction of apoptosis of TX803 in cancer cell lines
  • Apoptosis was measured by Western blotting.
  • Cell lysates were prepared by cell incubation in radio immunoprecipitation assay buffer (RTPA: 50 mmol/L Tris (pH 7.4), 150 mmol/L NaCl, 5 mmol/L EDTA, 1% Triton X-100, 1% Sodium deoxycholic acid, 0.1% SDS, 2 mmol/L phenylmethylsulfonyl fluoride (PMSF), 30 mmol/L Na 2 HP0 4 , 50 mmol/L NaF, and 1 mmol/L Na 3 V0 4 ).
  • RTPA radio immunoprecipitation assay buffer
  • PMSF phenylmethylsulfonyl fluoride
  • Cell lysates were then boiled in SDS sample loading buffer, resolved by 10% SDS-PAGE, and transferred to nitrocellulose membranes.
  • the membranes were blocked in 5% milk in TBST (10 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.05% Tween 20) for 1 hour at room temperature.
  • TBST 10 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.05% Tween 20
  • Membranes were then washed three times with TBST and immunoreactive products were visualized using enhanced chemiluminescence reagents and autoradiography.
  • SW620 cells were cultured in medium with 0% FBS and treated with TX803 (0, 2.5, 5, 10, 20, and 40 uM) for 6 hours followed by analysis by Western blotting.
  • HCT116 cells were cultured in medium with 0% FBS and treated with TX803 (0, 1.25, 2.5, 5, 10, and 20 uM) for 6 hours followed by analysis by Western blotting.
  • H292 cells were cultured in medium with 0% FBS and treated with TX803 (0, 2.5, 5, 10, and 20 uM) for 6 hours followed by analysis by Western blotting.
  • MCF-7 cells were cultured in medium with 0% FBS and treated with TX803 (0, 2.5, 5, 10, and 20 uM) for 8 hours followed by analysis by Western blotting.
  • FIG. 9E the apoptotic effects of TX803 were assayed in MDA-MB-231 cells.
  • MDA-MB-231 cells were cultured in medium with 0% FBS and treated with TX803 (0, 2.5, 5, 10, and 20 uM) for 6 hours 30 minutes followed by analysis by Western blotting.
  • FIG 10A apoptotic effects of TX803 and T Fa combination were measured in SW620 cells.
  • SW620 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 8 hours.
  • Apoptosis was analyzed by Western blotting.
  • HCT116 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 6 hours. Apoptosis was analyzed by Western blotting.
  • HT-29 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 6 hours. Apoptosis was analyzed by Western blotting.
  • apoptotic effects of TX803 and TNFa combination were measured in HepG2 cells.
  • HepG2 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 6 hours.
  • TX803 10 uM
  • TNFa 25 ng/ml
  • T: TNFa TNFa
  • H292 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 6 hours. Apoptosis was analyzed by Western blotting.
  • Apoptotic effects of TX803 and TNFa combination were measured in A549 cells.
  • A549 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 8 hours.
  • TNFa 25 ng/ml, T: TNFa
  • Apoptosis was analyzed by Western blotting.
  • MCF-7 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 8 hours. Apoptosis was analyzed by Western blotting.
  • MDA-MB-231 cells were cultured in medium with 0% FBS and treated with TX803 (10 uM) for 1 1 hour followed by TNFa (25 ng/ml, T: TNFa) for 6 hours and 30 minutes. Apoptosis was analyzed by Western blotting.
  • TX803 Growth inhibition assay of TX803 in different cancer cell lines demonstrated that TX803 was sensitive toward colon cancer cells. TX803 induced apoptosis in most cancer cell lines. The degree of apoptosis was enhanced by TX803 and TNFa combination.
  • Example 5 TX803 and Cobimetinib treatment in mouse tumor model
  • a MMTV-PyMT mouse breast cancer model was used to test the effects of TX803 and Cobimetinib treatment.
  • TX803 was dissolved in DMSO and diluted with normal saline containing 5.0% (WIN) Tween-80 to a final concentration 3 mg/mL.
  • Cobimetinib was dissolved in DMSO and diluted with normal saline containing 5.0% (V/V) Tween-80 to a final concentration 1 mg/mL. Normal saline with DMSO and 5.0% Tween-80 was employed as the vehicle control.
  • tissues from MMTV-PyMT mice of 14 weeks of age were harvested by grinding the tissue with a tissue disruptor on ice and lysing with buffer. Tissue extract was centrifuged at 12000 rpm for 10 minutes. The supernatant was added at an equal volume of 2X SDS. Samples were then boiled, resolved by SDS-PAGE, and transferred to a PVDF membrane. The PVDF membrane was blocked in milk, washed with TBST, and incubated with primary antibody. Following incubation with primary antibody, the PVDF membrane was washed and incubated with secondary antibody. Proteins were detected with ECLA and ECLB.
  • Tumor tissues were fixed with 10% buffered formalin in PBS and embedded in paraffin. Tumor sections (4 ⁇ ) were stained with hematoxylin and eosin (H&E).
  • ANOVA with Tukey's post-test was used for comparisons between groups. Two-way ANOVA was used for comparisons of magnitude of changes between different groups and to compare values among different experimental groups. For experiments with only two groups, Student's t-test was used. P ⁇ 0.05 was considered statistically significant (*), P ⁇ 0.01 as highly significant (**), P ⁇ 0.001 as extremely significant (***), and ns as not significant.
  • TX803 alone or in combination with Cobimetinib had little effect on the body weight as compared to vehicle control.
  • the data was consistent with a lack of toxicity of the drug at this dose.
  • Administration of Cobimetinib at 10 mg/kg to mice for 14 days resulted in a 23.33% decrease in body weight.
  • administration of TX830 alone at 30 mg/kg resulted in a significant inhibition (-48%) of tumor growth.
  • TX803 and Cobimetinib combination therapy achieved better efficacy on tumor growth inhibition, while on a dose reduction treatment regimen for the MEK inhibitor to alleviate toxicity.
  • Synergistic inhibition by TX803 and Cobimetinib combination on tumor growth suggests that ERK activation by TX803 serves as an escape mechanism by which tumor cells develop resistance to TX803 treatment.
  • a PDX colon cancer model was used to assay the effects of TX803.
  • TX803 was formulated in 0.5% Carboxymethyl cellulose Sodium (CMC-Na) with 0.2% Tween 80 at 3 mg/mL as a uniform suspension.
  • CMC-Na Carboxymethyl cellulose Sodium
  • Tween 80 was formulated in 0.5% CMC-Na with 0.2%) Tween 80 at 0.5 mg/mL as a uniform suspension.
  • TX803 was effective against this KRAS mutated tumor model following once-a-day oral treatment for 4 weeks. Further, TX803 mono-therapy was as effective as a combination therapy with a MEK inhibitor Cobimetinib (Figure 13). As seen in Figure 14, all treatments were well tolerated and there was no difference in body weight changes between the vehicle control and either treatment group.
  • Example 7 Preparation of pharmaceutical dosage forms - oral tablet
  • a tablet is prepared by mixing 48%> by weight of TX803, or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low- substituted hydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 250- 500 mg.

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Abstract

L'invention concerne des composés, des compositions pharmaceutiques et des méthodes d'utilisation desdits composés, et des compositions pour le traitement de cancer et d'autres troubles néoplasiques.
PCT/US2017/031427 2016-05-06 2017-05-05 Composés et méthodes thérapeutiques WO2017193086A1 (fr)

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CN109010919A (zh) * 2018-07-12 2018-12-18 南京航空航天大学 Pda涂层增强硅酸三钙生物活性的短流程制备方法

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