WO2013175474A2 - Selective inhibitors of undifferentiated cells - Google Patents

Selective inhibitors of undifferentiated cells Download PDF

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Publication number
WO2013175474A2
WO2013175474A2 PCT/IL2013/050441 IL2013050441W WO2013175474A2 WO 2013175474 A2 WO2013175474 A2 WO 2013175474A2 IL 2013050441 W IL2013050441 W IL 2013050441W WO 2013175474 A2 WO2013175474 A2 WO 2013175474A2
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WO
WIPO (PCT)
Prior art keywords
cells
undifferentiated
cancer
plurisin
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/IL2013/050441
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English (en)
French (fr)
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WO2013175474A3 (en
WO2013175474A9 (en
Inventor
Uri BEN-DAVID
Nissim Benvenisty
Payal ARORA
Qing-Fen Gan
Ralph J. GARIPPA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Yissum Research Development Co of Hebrew University of Jerusalem
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Yissum Research Development Co of Hebrew University of Jerusalem
Hoffmann La Roche Inc
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Publication date
Priority to KR1020147035024A priority Critical patent/KR20150013777A/ko
Priority to US14/402,467 priority patent/US9456998B2/en
Priority to EP13733462.9A priority patent/EP2852387A2/en
Priority to CN201380038889.6A priority patent/CN104768549A/zh
Priority to CA2873817A priority patent/CA2873817A1/en
Priority to RU2014149559A priority patent/RU2014149559A/ru
Priority to JP2015513349A priority patent/JP6293127B2/ja
Priority to MX2014014174A priority patent/MX2014014174A/es
Priority to BR112014029365A priority patent/BR112014029365A2/pt
Application filed by F Hoffmann La Roche AG, Yissum Research Development Co of Hebrew University of Jerusalem, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2013175474A2 publication Critical patent/WO2013175474A2/en
Publication of WO2013175474A3 publication Critical patent/WO2013175474A3/en
Publication of WO2013175474A9 publication Critical patent/WO2013175474A9/en
Anticipated expiration legal-status Critical
Priority to US15/259,119 priority patent/US20170027890A1/en
Priority to US15/885,872 priority patent/US20180153830A1/en
Ceased legal-status Critical Current

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    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Definitions

  • Tumor formation was reported to positively correlate with the residual presence of undifferentiated pluripotent cells [Miura et al., Nature Biotechnology 27:743-745 (2009)]. Very few hPSCs are required for teratoma formation [Lee et al., Cell Cycle 8:2608-2612 (2009); Hentze et al., Stem Cell Research 2: 198-210 (2009)], and even after prolonged differentiation in culture some tumorigenic pluripotent cells remain [Narsinh et al., Journal of Clinical Investigation 121: 1217-1221 (2011); Ghosh et al., Cancer Research 71:5030-5039 (2011); Fu et al., Stem Cells and Development 21:521- 529 (2012)].
  • Oleic acid the product of SCD1 activity, has been reported to compete with the saturated fatty acids, block the abnormal lipid distribution, and attenuate ER stress [Peng et al., Endocrinology 152:2206-2218 (2011); Hapala et al., Biology of the Cell / under the auspices of the European Cell Biology Organization 103:271-285 (2011)].
  • FIG. 4 presents fluorescent microscopy images of genetically labeled CSES2- S02/ human embryonic stem cells showing fluorescence-labeled Oct-4, 48 and 96 hours after being seeded in 384- well plates;
  • FIG. 16 is a scatter plot showing inhibition of CSES2 cells and fibroblasts by 20 ⁇ of exemplary compounds (data shown only for compounds inhibiting CSES2 cells by over 60 , selective inhibitors of CSES2 cells (less than 20 % inhibition of fibroblasts) are indicated by rectangle);
  • contacting the undifferentiated cells (e.g., pluripotent stem cells) with the compounds as described herein is effected in vitro.
  • a compound as described herein for use as a cytotoxic inhibitor of undifferentiated cells (e.g., pluripotent stem cells, undifferentiated cancer cells) or in a method of inhibiting undifferentiated cells (e.g., pluripotent stem cells, undifferentiated cancer cells).
  • undifferentiated cells e.g., pluripotent stem cells, undifferentiated cancer cells
  • a method of inhibiting undifferentiated cells e.g., pluripotent stem cells, undifferentiated cancer cells.
  • Subjects undergoing stem cell therapy can be, for example, subjects who suffered, prior to undergoing stem cell therapy, from diseases or disorders which are treatable by stem cell therapy.
  • diseases and disorders include, but are not limited to, cancer, Type I diabetes mellitus, Parkinson's disease, Huntington's disease, Alzheimer's disease, brain damage, spinal cord injury, celiac disease, cardiac failure, heart damage, anemia, baldness, deafness, blindness, vision impairment, amyotrophic lateral sclerosis, graft vs. host disease, Crohn's disease, infertility, wounds, orthopedic diseases or disorders, muscle damage and neurological disorders.
  • thiohydroxy describes a -SH group.
  • the pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically (including ophthalmically, vaginally, rectally, intranasally).
  • the SCDl inhibitor is A939572, CVT-11127 and/or GSK-993.
  • RNA interference refers to the process of sequence- specific post-transcriptional gene silencing in animals mediated by short interfering RNAs (siRNAs).
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • isopropanol was obtained from Sigma- Aldrich;
  • M2 medium was obtained from Sigma-Aldrich
  • RPMI- 1640 medium was obtained from Invitrogen;
  • Human embryonic stem cell-derived hepatocytes were obtained from Cellartis (Goteborg, Sweden), and handled according to the manufacturer's instructions;
  • a 52,448 compound screening library assembled with Roche internal compounds (referred to as the "golden” library) was tested in a 384-well format.
  • Compounds were distributed in 384-well plates (352 compounds per plate) as 0.5 ⁇ of 4 mM DMSO solutions.
  • counter- screens and compound profiling screens compounds that were defined as "hits” were obtained from a Roche proprietary compound inventory, and distributed in a 384-well format as 8 ⁇ of 5 mM DMSO solutions.
  • Cells were then harvested and seeded in 384-well plates, at a density of 5,000 cells per well. Quantitative PCR and immunofluorescence- staining for Oct-4 and NANOG were performed in order to verify that the cells remained undifferentiated for at least 5 days under these conditions.
  • CellTiter-Glo® An ATP-based luminescent cell viability assay (CellTiter-Glo®) was used to accurately measure of the amount of living cells in a culture of undifferentiated cells, as described hereinabove.
  • a pilot screen was then performed with 50 commercially-available compounds (as described in the Materials and Methods section hereinabove), which were randomly selected from a bank of known cytotoxic compounds.
  • Cells were exposed to the compounds at 5 different concentrations ranging from 30 ⁇ to 300 nM, for 4 exposure durations (6, 24, 48 or 72 hours), and were then subjected to the viability assay.
  • all of the tested compounds which exhibited observable cytotoxicity exhibited such activity at 24 hours.
  • a test period of 24 hours was therefore chosen for the following primary screen.
  • PluriSIn #6 eliminated the red undifferentiated cells without exhibiting any detectable effect on the green differentiated cells.
  • the effect of the PluriSIn on the undifferentiated cells was comparable to that of 5 ⁇ amsacrine hydrochloride, used as a cytotoxic control compound, whereas the PluriSIn-treated differentiated cells were comparable to untreated differentiated cells.
  • BSA-OA protected cells against PluriSIn #1- induced apoptosis in a dose-dependent manner, with full rescue occurring in the presence of high concentrations, whereas BSA alone did not afford any protection against apoptosis.
  • this protection was specific, as BSA-OA did not affect proliferation in the control cells, and did not protect cells against the cytotoxicity of a DNA-topoisomerase inhibitor (amsacrine, Figure 47).
  • mPSCs Mouse pluripotent stem cells
  • PluriSIns #1, #2, #4 or #6 PluriSIns #1, #2, #4 or #6 at a concentration of 20 ⁇ , and the viability of the cells was then assessed after 24 hours, 48 hours and 72 hours, using a luminescent viability assay and fluorescent microscopy imaging, as described in the Materials and Methods section.
  • blastocysts are shown in Figure 58, showing good quality control blastocysts and PluriSIn-treated blastocysts, bad quality PluriSIn- treated blastocysts, and PluriSIn-treated embryos stuck at the morula stage.
  • oleic acid supplementation rescued most embryos from the effects of PluriSIn #1, with 5 of 7 oleic acid- supplemented embryos (71 %) developing into high-quality blastocysts, as opposed to 7 of 17 (41 %) in the absence of oleic acid.
  • mice All mice (3/3) injected with control H9 ES cells developed teratomas, whereas none of the mice (0/3) injected with PluriSIn #l-treated H9 ES cells developed teratomas.
  • SCDl inhibition in general can inhibit pluripotent stem cells
  • SCDl expression was inhibited using siRNA knockdown of the SCDl gene, using procedures described in the Materials and Methods section. Untreated cells and cells treated with mock siRNA were used as a control. The viability of the pluripotent stem cells was then determined.

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