EP3110421A2 - Brustkrebszellwachstum-hemmende enzyminhibitoren, verfahren zu ihrer herstellung sowie deren verwendung - Google Patents

Brustkrebszellwachstum-hemmende enzyminhibitoren, verfahren zu ihrer herstellung sowie deren verwendung

Info

Publication number
EP3110421A2
EP3110421A2 EP14799883.5A EP14799883A EP3110421A2 EP 3110421 A2 EP3110421 A2 EP 3110421A2 EP 14799883 A EP14799883 A EP 14799883A EP 3110421 A2 EP3110421 A2 EP 3110421A2
Authority
EP
European Patent Office
Prior art keywords
breast cancer
enzyme inhibitors
cell growth
halogen
cancer cell
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.)
Withdrawn
Application number
EP14799883.5A
Other languages
German (de)
English (en)
French (fr)
Inventor
Andreas Hilgeroth
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.)
Martin Luther Universitaet Halle Wittenberg
Original Assignee
Martin Luther Universitaet Halle Wittenberg
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Martin Luther Universitaet Halle Wittenberg filed Critical Martin Luther Universitaet Halle Wittenberg
Publication of EP3110421A2 publication Critical patent/EP3110421A2/de
Withdrawn legal-status Critical Current

Links

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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Breast cancer is the most common cancer in women according to epidemiological data [1]. Particularly aggressive breast cancers are characterized by invasive and metastatic behavior [2]. The therapy of such aggressive breast cancers is extremely problematic and very costly through the use of specific antibodies, which only take place with multiple positive histochemical tests [3].
  • a second factor plays a further important role in aggressive breast cancers. It is the enzyme Brk that is overexpressed in the aggressive tumor cells such as HER2 [2,4,7]. Here, the activity of HER2 is further enhanced by Brk [2,7]. Thus, Brk not only increases the uncontrolled growth of tumor cells, but also inhibits their apoptosis [2,8-1 1]. The aggressiveness of the tumor cells is further increased by Brk, that a metastasis is increased [2]. This is a consequence of the non-dying of the tumor cells after their detachment from the tumor cell structure and the formation of its own tumor cell association [2].
  • the object of the invention is the development of new enzyme inhibitors by the combination in the inhibition of enzymes which fight both synergistically and additively the aggressive breast cell growth.
  • An existing resistance to inhibitors is overcome by the new inhibitors, an emerging resistance in the course of therapy can be prevented by the principle of action.
  • the pyridoanilated indoles developed according to the invention have a selective inhibiting effect on the enzymes HER2 and / or Brk in the nanomolar to picomolar concentration range in a screening of over 200 kinases of the human kinome. In dual inhibition, the hitherto impossible therapy of resistant tumors is given. In addition, a resistance formation is prevented.
  • the enzyme inhibitors developed according to the invention inhibit the growth of breast cancer cells in the nanomolar concentration range without exhibiting critical toxic effects. Here they differ from other tumor therapeutics, which have side effects and are therefore poorly tolerated with cytotoxic effects in therapy.
  • the derivatization in the 6-position of 4-chloro-carboline succeeds byproduct-free and takes place as well as the derivatization in position 4 with the aniline derivatives in high purity with quantitative yields.
  • the inhibition of the enzymes Brk and HER was performed with radioactively labeled ATP-enriched ATP and the substrate poly (Gly, Tyr) 4: 1 with various concentrations of the inhibitors in HEPES buffer solution.
  • the percentage inhibition of the enzymes is determined by means of the measured substrate phosphorylation by means of scintillation measurement. From the percentage inhibition the IC50 of enzyme inhibition was calculated. It was an aniline derivative substituted for a meta-chloro for the inhibition of Brk 5 nM and of HER2 66 nM.
  • the breast cancer cell growth inhibitory activity was determined in the sulforhodamine B assay.
  • the various breast cancer cell lines were cultured in RPMI 1640 medium containing 5% fetal calf serum and 2 nM L-glutamine. After 24 hours of cultivation at 37 ° C and 100% humidity in C0 2 atmosphere (5%) was incubated with various inhibitor concentrations in microtiter plates. Subsequently, the adherent cells were fixed with 50% Tichloroacetic acid. After renewed incubation, the supernatant was discarded, the cells washed with sulforhodamine B solution in acetic acid.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP14799883.5A 2013-06-26 2014-08-21 Brustkrebszellwachstum-hemmende enzyminhibitoren, verfahren zu ihrer herstellung sowie deren verwendung Withdrawn EP3110421A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102013010603.6A DE102013010603A1 (de) 2013-06-26 2013-06-26 Brustkrebszellwachstum-hemmende Enzyminhibitoren, Verfahren zu ihrer Herstellung sowie deren Verwendung
PCT/IB2014/002141 WO2014207573A2 (de) 2013-06-26 2014-08-21 Brustkrebszellwachstum-hemmende enzyminhibitoren, verfahren zu ihrer herstellung sowie deren verwendung

Publications (1)

Publication Number Publication Date
EP3110421A2 true EP3110421A2 (de) 2017-01-04

Family

ID=51905309

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14799883.5A Withdrawn EP3110421A2 (de) 2013-06-26 2014-08-21 Brustkrebszellwachstum-hemmende enzyminhibitoren, verfahren zu ihrer herstellung sowie deren verwendung

Country Status (5)

Country Link
US (1) US9901570B2 (ja)
EP (1) EP3110421A2 (ja)
JP (1) JP2016530228A (ja)
DE (1) DE102013010603A1 (ja)
WO (1) WO2014207573A2 (ja)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017066193A1 (en) 2015-10-15 2017-04-20 Princeton Drug Discovery, Llc Novel inhibitors of protein kinases
US11773093B1 (en) * 2023-01-19 2023-10-03 King Faisal University N-(pyrimido[2,3-b]indol-7-yl)acetamide compounds as antibacterial agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006131552A1 (de) * 2005-06-09 2006-12-14 Boehringer Ingelheim International Gmbh Alpha-carboline als cdk-1 inhibitoren
EP2161271A1 (en) * 2008-09-08 2010-03-10 Università Degli Studi Di Milano - Bicocca Alpha-carboline inhibitors of NMP-ALK, RET, and Bcr-Abl
EP2662372A1 (en) * 2012-05-11 2013-11-13 Università Degli Studi Di Milano - Bicocca Alpha-carbolines for the treatment of cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014207573A2 *

Also Published As

Publication number Publication date
WO2014207573A2 (de) 2014-12-31
WO2014207573A3 (de) 2015-05-14
WO2014207573A8 (de) 2015-03-26
US9901570B2 (en) 2018-02-27
JP2016530228A (ja) 2016-09-29
DE102013010603A1 (de) 2014-12-31
US20160235723A1 (en) 2016-08-18

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