MX2020010121A - Compuestos con actividad antitumoral contra celulas de cancer que portan las mutaciones del exon 19 del receptor 2 del factor de crecimiento epidermico humano. - Google Patents
Compuestos con actividad antitumoral contra celulas de cancer que portan las mutaciones del exon 19 del receptor 2 del factor de crecimiento epidermico humano.Info
- Publication number
- MX2020010121A MX2020010121A MX2020010121A MX2020010121A MX2020010121A MX 2020010121 A MX2020010121 A MX 2020010121A MX 2020010121 A MX2020010121 A MX 2020010121A MX 2020010121 A MX2020010121 A MX 2020010121A MX 2020010121 A MX2020010121 A MX 2020010121A
- Authority
- MX
- Mexico
- Prior art keywords
- mutations
- compounds
- cancer cells
- activity against
- tumor activity
- Prior art date
Links
- 230000035772 mutation Effects 0.000 title abstract 3
- 206010028980 Neoplasm Diseases 0.000 title abstract 2
- 201000011510 cancer Diseases 0.000 title abstract 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 title 1
- 230000000259 anti-tumor effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 title 1
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 abstract 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 abstract 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 abstract 1
- 229950009876 poziotinib Drugs 0.000 abstract 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 abstract 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 abstract 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 abstract 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
-
- 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
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Pathology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
La presente divulgación proporciona métodos para tratar cáncer en un paciente que tiene una mutación del exón 19 de HER2 tal como una mutación genética, al administrar un inhibidor de tirosina quinasa de tercera generación, tal como poziotinib.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862648629P | 2018-03-27 | 2018-03-27 | |
| US201862688049P | 2018-06-21 | 2018-06-21 | |
| PCT/US2019/024353 WO2019191279A2 (en) | 2018-03-27 | 2019-03-27 | Compounds with anti-tumor activity against cancer cells bearing her2 exon 19 mutations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2020010121A true MX2020010121A (es) | 2021-01-08 |
Family
ID=68060750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2020010121A MX2020010121A (es) | 2018-03-27 | 2019-03-27 | Compuestos con actividad antitumoral contra celulas de cancer que portan las mutaciones del exon 19 del receptor 2 del factor de crecimiento epidermico humano. |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US20210361655A1 (es) |
| EP (1) | EP3773551A4 (es) |
| JP (1) | JP7386174B2 (es) |
| KR (1) | KR20200136417A (es) |
| CN (1) | CN112088000A (es) |
| AU (1) | AU2019243738B2 (es) |
| BR (1) | BR112020019251A2 (es) |
| CA (1) | CA3094108A1 (es) |
| IL (1) | IL277373A (es) |
| MX (1) | MX2020010121A (es) |
| PH (1) | PH12020551495A1 (es) |
| RU (1) | RU2020134932A (es) |
| SG (1) | SG11202009498RA (es) |
| WO (1) | WO2019191279A2 (es) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2021007554A (es) * | 2018-12-21 | 2021-08-11 | Univ Texas | Terapia de combinacion para el tratamiento de cancer. |
| US20220143023A1 (en) * | 2019-03-29 | 2022-05-12 | Board Of Regents, The University Of Texas System | Compounds with anti-tumor activity against cancer cells bearing egfr or her2 exon 20 insertions |
| JP2022529945A (ja) * | 2019-04-17 | 2022-06-27 | ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム | チロシンキナーゼ阻害剤耐性ｅｇｆｒ変異を有するがんに対する化合物 |
Family Cites Families (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5824311A (en) | 1987-11-30 | 1998-10-20 | Trustees Of The University Of Pennsylvania | Treatment of tumors with monoclonal antibodies against oncogene antigens |
| US4870287A (en) | 1988-03-03 | 1989-09-26 | Loma Linda University Medical Center | Multi-station proton beam therapy system |
| US5288644A (en) | 1990-04-04 | 1994-02-22 | The Rockefeller University | Instrument and method for the sequencing of genome |
| US5851795A (en) | 1991-06-27 | 1998-12-22 | Bristol-Myers Squibb Company | Soluble CTLA4 molecules and uses thereof |
| US5801029A (en) | 1993-02-16 | 1998-09-01 | Onyx Pharmaceuticals, Inc. | Cytopathic viruses for therapy and prophylaxis of neoplasia |
| US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
| JPH08506247A (ja) | 1993-07-09 | 1996-07-09 | アムジェン ボールダー インコーポレイテッド | 組換えｃｔｌａ４ポリペプチドおよびその製造方法 |
| GB9506466D0 (en) | 1994-08-26 | 1995-05-17 | Prolifix Ltd | Cell cycle regulated repressor and dna element |
| US5760395A (en) | 1996-04-18 | 1998-06-02 | Universities Research Assoc., Inc. | Method and apparatus for laser-controlled proton beam radiology |
| US5739169A (en) | 1996-05-31 | 1998-04-14 | Procept, Incorporated | Aromatic compounds for inhibiting immune response |
| US5869245A (en) | 1996-06-05 | 1999-02-09 | Fox Chase Cancer Center | Mismatch endonuclease and its use in identifying mutations in targeted polynucleotide strands |
| US5844905A (en) | 1996-07-09 | 1998-12-01 | International Business Machines Corporation | Extensions to distributed MAC protocols with collision avoidance using RTS/CTS exchange |
| WO1998042752A1 (en) | 1997-03-21 | 1998-10-01 | Brigham And Women's Hospital Inc. | Immunotherapeutic ctla-4 binding peptides |
| US6723564B2 (en) | 1998-05-07 | 2004-04-20 | Sequenom, Inc. | IR MALDI mass spectrometry of nucleic acids using liquid matrices |
| EP2112166B1 (en) | 1998-12-23 | 2018-11-21 | Pfizer Inc. | Human monoclonal antibodies to ctla-4 |
| DE60033530T2 (de) | 1999-08-24 | 2007-10-31 | Medarex Inc. | Humane antikörper gegen ctla-4 und deren verwendungen |
| US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
| US7935500B2 (en) | 2002-03-26 | 2011-05-03 | Massachusetts Institute Of Technology | Identifying calcineurin activators for treatment of schizophrenia |
| US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
| US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
| SI2161336T1 (sl) | 2005-05-09 | 2013-11-29 | Ono Pharmaceutical Co., Ltd. | Humana monoklonska protitelesa za programirano smrt 1 (PD-1) in postopki za zdravljenje raka ob uporabi anti-PD-1 protiteles samih ali v kombinaciji z drugimi imunoterapevtiki |
| TWI377944B (en) | 2007-06-05 | 2012-12-01 | Hanmi Holdings Co Ltd | Novel amide derivative for inhibiting the growth of cancer cells |
| EP2535354B1 (en) | 2007-06-18 | 2017-01-11 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
| CN104548091A (zh) | 2008-02-11 | 2015-04-29 | 治疗科技公司 | 用于肿瘤治疗的单克隆抗体 |
| US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
| WO2010014784A2 (en) | 2008-08-01 | 2010-02-04 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases |
| US20110223188A1 (en) | 2008-08-25 | 2011-09-15 | Solomon Langermann | Targeted costimulatory polypeptides and methods of use to treat cancer |
| US20130017199A1 (en) | 2009-11-24 | 2013-01-17 | AMPLIMMUNE ,Inc. a corporation | Simultaneous inhibition of pd-l1/pd-l2 |
| ES2586579T3 (es) | 2010-02-19 | 2016-10-17 | Xencor, Inc. | Nuevas inmunoadhesinas de CTLA4-IG |
| KR101217526B1 (ko) | 2010-06-11 | 2013-01-02 | 한미사이언스 주식회사 | 아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물 |
| US8828391B2 (en) | 2011-05-17 | 2014-09-09 | Boehringer Ingelheim International Gmbh | Method for EGFR directed combination treatment of non-small cell lung cancer |
| KR101317809B1 (ko) | 2011-06-07 | 2013-10-16 | 한미약품 주식회사 | 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물 |
| JP2014022858A (ja) | 2012-07-17 | 2014-02-03 | Murata Mfg Co Ltd | 電力増幅器 |
| US9308236B2 (en) | 2013-03-15 | 2016-04-12 | Bristol-Myers Squibb Company | Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions |
| AU2014296887A1 (en) | 2013-08-02 | 2016-01-28 | Aduro Biotech Holdings, Europe B.V. | Combining CD27 agonists and immune checkpoint inhibition for immune stimulation |
| US20180057603A1 (en) * | 2013-08-09 | 2018-03-01 | The Trustees Of The University Of Pennsylvania | Combination of IFN-gamma with Anti-ERBB Antibody for the Treatment of Cancers |
| CN107011441B (zh) | 2013-09-13 | 2020-12-01 | 百济神州(广州)生物科技有限公司 | 抗pd1抗体及其作为治疗剂与诊断剂的用途 |
| JP6782698B2 (ja) * | 2014-12-12 | 2020-11-11 | セルキュイティー インコーポレイテッド | がん患者を診断および処置するためのｅｒｂｂシグナル伝達経路活性の測定方法 |
| MX2021007554A (es) * | 2018-12-21 | 2021-08-11 | Univ Texas | Terapia de combinacion para el tratamiento de cancer. |
-
2019
- 2019-03-27 US US17/042,012 patent/US20210361655A1/en active Pending
- 2019-03-27 CN CN201980022143.3A patent/CN112088000A/zh active Pending
- 2019-03-27 SG SG11202009498RA patent/SG11202009498RA/en unknown
- 2019-03-27 JP JP2020551912A patent/JP7386174B2/ja active Active
- 2019-03-27 AU AU2019243738A patent/AU2019243738B2/en active Active
- 2019-03-27 BR BR112020019251-1A patent/BR112020019251A2/pt not_active IP Right Cessation
- 2019-03-27 MX MX2020010121A patent/MX2020010121A/es unknown
- 2019-03-27 CA CA3094108A patent/CA3094108A1/en active Pending
- 2019-03-27 WO PCT/US2019/024353 patent/WO2019191279A2/en unknown
- 2019-03-27 KR KR1020207029032A patent/KR20200136417A/ko unknown
- 2019-03-27 RU RU2020134932A patent/RU2020134932A/ru unknown
- 2019-03-27 EP EP19775368.4A patent/EP3773551A4/en active Pending
-
2020
- 2020-09-15 IL IL277373A patent/IL277373A/en unknown
- 2020-09-17 PH PH12020551495A patent/PH12020551495A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN112088000A (zh) | 2020-12-15 |
| CA3094108A1 (en) | 2019-10-03 |
| RU2020134932A (ru) | 2022-04-27 |
| BR112020019251A2 (pt) | 2021-01-12 |
| US20210361655A1 (en) | 2021-11-25 |
| WO2019191279A3 (en) | 2019-11-07 |
| PH12020551495A1 (en) | 2021-09-01 |
| JP7386174B2 (ja) | 2023-11-24 |
| KR20200136417A (ko) | 2020-12-07 |
| AU2019243738A1 (en) | 2020-10-08 |
| AU2019243738B2 (en) | 2024-05-30 |
| EP3773551A2 (en) | 2021-02-17 |
| WO2019191279A2 (en) | 2019-10-03 |
| SG11202009498RA (en) | 2020-10-29 |
| EP3773551A4 (en) | 2022-03-23 |
| JP2021519306A (ja) | 2021-08-10 |
| IL277373A (en) | 2020-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PH12019501116A1 (en) | Compounds with anti-tumor activity against cancer cells bearing egfr or her2 exon 20 | |
| MX2021011948A (es) | Compuestos con actividad antitumoral contra células cancerígenas que llevan inserciones de exon 20 effr o her2. | |
| PH12020551495A1 (en) | Compounds with anti-tumor activity against cancer cells bearing her2 exon 19 mutations | |
| WO2018049152A8 (en) | Pyrazolopyrimidine derivatives as hpk1 modulators and uses thereof for the treatment of cancer | |
| CR20220584A (es) | Inhibidores de kras tricíclicos fusionados | |
| EA201990665A1 (ru) | Регуляторы hpk1 на основе производных пиразолопиридина и их применение для лечения рака | |
| PH12016501394A1 (en) | Compounds for treating patients with ros1 mutant cancer cells | |
| MX2021011209A (es) | Novedosos inhibidores de molécula pequeña de factores de transcripción tead. | |
| MX2021011925A (es) | Compuestos con actividad antitumoral contra celulas cancerigenas que portan inserciones del exon 21 del receptor 2 del factor de crecimiento epidermico humano. | |
| PH12021550119A1 (en) | Pyridin-2-one compounds useful as smarca2 antagonists | |
| EA201390550A1 (ru) | Способы ингибирования пролиферации клеток в egfr-стимулируемых злокачественных опухолях | |
| MX354212B (es) | Derivados de piperidin-4-il azetidina como inhibidores de janus cinasa 1 (jak1). | |
| MX2019010149A (es) | Inhibicion del smarca2 para el tratamiento del cancer. | |
| MX2021012705A (es) | Compuestos con actividad antitumoral contra las celulas cancerosas que portan mutaciones en el receptor del factor de crecimiento epidermico (egfr) resistentes al inhibidor de la tirosina quinasa. | |
| CA2902116C (en) | Pyrrolopyridine derivatives and their use as inhibitors of ssao activity | |
| MX2019012176A (es) | Metodos de combinacion de chk1(sra737)/parpi para inhibir el crecimiento tumoral. | |
| PH12021551276A1 (en) | Combination therapy for the treatment of cancer | |
| PH12017500977A1 (en) | 1-[2-(aminomethyl)benzyl]-2-thioxo-1,2,3,5-tetrahydro-4h-pyrrolo[3,2-d]pyrimidin-4-ones as inhibitors of myeloperoxidase | |
| MX2020003126A (es) | Derivados de iminopirimidina ciclicos como inhibidores de cinasa. | |
| CR20240059A (es) | Compuestos tricíclicos como inhibidores de kras. | |
| EA201791179A1 (ru) | Дейтерированный триазолопиридазин в качестве модулятора киназы | |
| MX2023006434A (es) | Inhibidores de quinasa y usos de los mismos. | |
| MX2018006776A (es) | Usos de pirimido-piridazinonas para tratar el cancer. | |
| MX2021003182A (es) | Métodos para tratar trastornos mieloproliferativos. | |
| EA201991205A1 (ru) | Соединения с противоопухолевой активностью в отношении раковых клеток, несущих мутации в 20 экзоне egfr или her2 |