WO2005049032A1 - Inhibitors of the mutant form of kit - Google Patents

Inhibitors of the mutant form of kit Download PDF

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Publication number
WO2005049032A1
WO2005049032A1 PCT/EP2004/013045 EP2004013045W WO2005049032A1 WO 2005049032 A1 WO2005049032 A1 WO 2005049032A1 EP 2004013045 W EP2004013045 W EP 2004013045W WO 2005049032 A1 WO2005049032 A1 WO 2005049032A1
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WO
WIPO (PCT)
Prior art keywords
kit
del
inhibitor
mutant form
midostaurin
Prior art date
Application number
PCT/EP2004/013045
Other languages
French (fr)
Inventor
Elisabeth Buchdunger
Doriano Fabbro
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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Filing date
Publication date
Priority to DE602004020654T priority Critical patent/DE602004020654D1/en
Priority to AT04818795T priority patent/ATE428426T1/en
Priority to MXPA06005598A priority patent/MXPA06005598A/en
Priority to DK04818795T priority patent/DK1686997T3/en
Priority to SI200431159T priority patent/SI1686997T1/en
Priority to PL04818795T priority patent/PL1686997T3/en
Priority to CA2546189A priority patent/CA2546189C/en
Priority to US10/579,586 priority patent/US8017621B2/en
Priority to BRPI0416680-9A priority patent/BRPI0416680A/en
Priority to AU2004290902A priority patent/AU2004290902B2/en
Priority to EP04818795A priority patent/EP1686997B1/en
Priority to NZ547195A priority patent/NZ547195A/en
Priority to KR1020067009584A priority patent/KR101153647B1/en
Priority to JP2006540309A priority patent/JP4762150B2/en
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2005049032A1 publication Critical patent/WO2005049032A1/en
Priority to IL175578A priority patent/IL175578A/en
Priority to TNP2006000138A priority patent/TNSN06138A1/en
Priority to NO20062694A priority patent/NO20062694L/en
Priority to HK07100148.4A priority patent/HK1093680A1/en
Priority to HR20090390T priority patent/HRP20090390T1/en
Priority to US12/700,106 priority patent/US8124611B2/en
Priority to US13/357,972 priority patent/US20120157441A1/en
Priority to IL229124A priority patent/IL229124A0/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/44—Multiple drug resistance

Definitions

  • the present invention relates to the treatment of KIT dependent diseases that are characterized by a mutant form of KIT whereby the mutant KIT is identified and an appropriate inhibitor of the mutant KIT is administered.
  • the c-kit gene encodes a receptor protein tyrosine kinase, which is herein referred to as KIT, but which is also known as mast/stem cell growth factor receptor.
  • KIT receptor protein tyrosine kinase
  • the amino acid sequence of KIT and the nucleotide sequence of the c-kit gene are known. See Swiss Prot.: P10721. Upon binding its ligand, stem cell factor, KIT forms a dimer that is autophosphorylated and activates signaling cascades that lead to cell growth.
  • Mutations that lead to an activated form of KIT are known and are believed to play a role in certain proliferative diseases, such as mast cell diseases, like mastocytosis, particularly systemic mastocytosis, acute myelogenous leukemia, gastrointestinal stromal tumors, sinonasal NK/T-cell lymphoma, seminomas and dysgerminomas.
  • mast cell diseases like mastocytosis, particularly systemic mastocytosis, acute myelogenous leukemia, gastrointestinal stromal tumors, sinonasal NK/T-cell lymphoma, seminomas and dysgerminomas.
  • Imatinib which is marketed as its mesylate salt under the brandname GLIVEC or GLEEVEC, is known to inhibit wild type KIT and certain KIT mutations e.g. those in exons commonly found in gastrointestinal stromal tumors (GIST). However, it is also inactive or significantly less active against certain other mutant forms of KIT, for example the D816V mutation commonly found in systemic mastocytosis.
  • the present invention is based upon research that correlates the treatment of a disease characterized by a mutant form of KIT with an appropriate alternative pharmaceutical therapy based on the alternative's ability to inhibit the mutant KIT.
  • the present invention relates to a method of treating a KIT dependent disease in a patient, which comprises (a) identifying the mutant form of KIT associated with the KIT dependent disease; and (b) administering to the patient an effective mutant KIT-inhibiting amount of an inhibitor selected from the group consisting of midostaurin, vatalanib and compound A.
  • KIT dependent diseases are generally proliferative diseases that are characterized by excessive KIT kinase activity due to an activating mutation in KIT. Such activating mutations are known in the art and are identified by techniques known in the art.
  • KIT dependent diseases include diseases characterized by the following known KIT mutations: D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557- 561, N822K, V654A, N822H, Del 550-558 + V654A, Del 557-561 + V654A, lns503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801 I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I.
  • the KIT dependent disease is resistant to treatment with imatinib.
  • a KIT dependent disease that is resistant to imatinib is generally a KIT dependent disease as described above wherein imatinib, administered at a dose of 400-1000 mg/day, does not provide sufficient inhibition of the mutant KIT to effect a significant therapeutic benefit.
  • mutant KIT that is resistant to imatinib has an in vitro IC 50 of the mutant KIT greater than about 3 micromolar.
  • Imatinib resistant KIT mutations include D816F, D816H, D816N, D816Y, D816V, T670I and mutant forms that include V654A.
  • the selection of a compound that inhibits the mutant form of KIT is based on testing the compound or a number of compounds for their ability to inhibit the mutant KIT. Such testing is carried out by standard inhibition assays that are known in the art or within the skill of the artisan.
  • the KIT inhibitors utilized in accordance with the present method include midostaurin, vatalanib and compound A.
  • Midostaurin US5;093,330
  • vatalanib WO 98/35958
  • Compound A is a compound of the formula
  • An appropriate dose of midostaurin is administered, e.g., once, twice or three times a day, for a total dose of 25 - 300 preferably 50-300 more preferably 50 -100 most preferably 100-300 mg daily, e.g., two or three times a day, for a total dose of 150-250 mg, preferably 225 mg daily.
  • An appropriate daily dose of vatanalib is an amount in the range from 300-4000 mg, e.g., in the range from 300-2000 mg/day or 300-1500 mg/day, in particular, 300, 500, 750, 1000, 1250, 1500 or 2000 mg/day, particularly 1250 mg/day.
  • the daily dose of compound A for a 70 kg/person is from approximately 0.05-5 g, preferably from approximately 0.25-1.5 g.
  • the human KIT gene encoding aa 544-976 was cloned into the baculovirus donor plasmid pFB-GST-01. This coding sequence was excised using restriction endonucleases Bam H1 and EcoRI and ligated to a Bac-to-Bac donor vector pFB-GEX-P1 with compatible ends. Subsequently the desired mutations were brought into the KIT gene by methods know to a person skilled in the art.
  • the mutated plasmid inserts were excised and inserted into the Bac-to-Bac donor vector pFB-GST-01 using the restriction enzymes BamH1-EcoR1 for each mutant shown in Figure 1. Automated sequencing confirmed the correct sequence to be present for each mutant plasmid.
  • Bacmid DNA was generated from 10 colonies each of DHIOBac cells transformed with pFB-GO1-KIT-mutant plasmid clones as described in materials and methods and these transfected into Sf9 cells.
  • the transfected cells were pelleted and the resultant recombinant baculovirus present in the supernatant medium amplified.
  • Western blotting was applied to the lysed cell pellets to confirm the expression of the GST-c-KIT fusion protein by the viral clones using anti-KIT and anti-GST antibodies for immonudetection.
  • Virus containing media was collected from the transfected cell culture and used for infection to increase its titer. Virus containing media obtained after two rounds of infection was used for large-scale protein expression. For large-scale protein expression 100 cm 2 round tissue culture plates were seeded with 5 x 10 7 cells/plate and infected with 1 mL of virus-containing media (approximately 5 MOls). After 3 days, the cells were scraped off the plate and centrifuged at 500 rpm for 5 minutes.
  • ice-cold lysis buffer 25 mM Tris-HCI, pH 7.5, 2 mM EDTA, 1 % NP-40, 1 mM DTT, 1 mM PMSF.
  • the centrifuged cell lysate was loaded onto a 2 mL glutathione-sepharose column (Pharmacia) and washed 3 x with 10 mL of 25 mM Tris-HCI, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCI.
  • the GST-tagged proteins were then eluted by 10 applications (1 mL each) of 25 mM Tris-HCI, pH 7.5, 10 mM reduced-glutathione, 100 mM NaCI, 1 mM DTT, 10% glycerol and stored at -70°C.
  • the protein kinase activities of the various Kit mutants 200-500 ng were assayed in the presence or absence of inhibitors, 20 mM Tris-HCI, pH 7.6, 3 mM MnCI 2 , 3 mM MgCI 2 , 1 mM DTT, 10 ⁇ M Na 3 VO 4 , 3 ⁇ g/mL poly(Glu.Tyr) 4:1 , 1% DMSO, 1.5 ⁇ M ATP ( ⁇ -[ 33 P]-ATP 0.1 ⁇ Ci).
  • the assay (30 ⁇ L) was carried out in 96-well plates at ambient temperature for 30 minutes and the reaction terminated by the addition of 20 ⁇ L of 125 mM EDTA.
  • IC 50 values were calculated by linear regression analysis of the percentage inhibition of each compound in duplicate, at 4 concentrations (usually 0.01 , 0.1 , 1 and 10 ⁇ M).
  • One unit of protein kinase activity is defined as 1 nmole of 33 P transferred from [ ⁇ 33 P]ATP to the substrate protein/minute/mg of protein at RT.

Abstract

The present invention relates to the treatment of KIT dependent diseases that are characterized by a mutant form of KIT whereby the mutant KIT is identified and an appropriate inhibitor of the mutant KIT selected form midostaurin, vatalanib and compound A is administered.

Description

Inhibitors of the mutant form of KIT
The present invention relates to the treatment of KIT dependent diseases that are characterized by a mutant form of KIT whereby the mutant KIT is identified and an appropriate inhibitor of the mutant KIT is administered.
The c-kit gene encodes a receptor protein tyrosine kinase, which is herein referred to as KIT, but which is also known as mast/stem cell growth factor receptor. The amino acid sequence of KIT and the nucleotide sequence of the c-kit gene are known. See Swiss Prot.: P10721. Upon binding its ligand, stem cell factor, KIT forms a dimer that is autophosphorylated and activates signaling cascades that lead to cell growth. Mutations that lead to an activated form of KIT, especially forms that are activated independently of its ligand, are known and are believed to play a role in certain proliferative diseases, such as mast cell diseases, like mastocytosis, particularly systemic mastocytosis, acute myelogenous leukemia, gastrointestinal stromal tumors, sinonasal NK/T-cell lymphoma, seminomas and dysgerminomas.
Imatinib, which is marketed as its mesylate salt under the brandname GLIVEC or GLEEVEC, is known to inhibit wild type KIT and certain KIT mutations e.g. those in exons commonly found in gastrointestinal stromal tumors (GIST). However, it is also inactive or significantly less active against certain other mutant forms of KIT, for example the D816V mutation commonly found in systemic mastocytosis. The present invention is based upon research that correlates the treatment of a disease characterized by a mutant form of KIT with an appropriate alternative pharmaceutical therapy based on the alternative's ability to inhibit the mutant KIT.
Thus, the present invention relates to a method of treating a KIT dependent disease in a patient, which comprises (a) identifying the mutant form of KIT associated with the KIT dependent disease; and (b) administering to the patient an effective mutant KIT-inhibiting amount of an inhibitor selected from the group consisting of midostaurin, vatalanib and compound A. KIT dependent diseases are generally proliferative diseases that are characterized by excessive KIT kinase activity due to an activating mutation in KIT. Such activating mutations are known in the art and are identified by techniques known in the art.
KIT dependent diseases include diseases characterized by the following known KIT mutations: D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557- 561, N822K, V654A, N822H, Del 550-558 + V654A, Del 557-561 + V654A, lns503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801 I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I.
In an important embodiment of the present invention, the KIT dependent disease is resistant to treatment with imatinib. A KIT dependent disease that is resistant to imatinib is generally a KIT dependent disease as described above wherein imatinib, administered at a dose of 400-1000 mg/day, does not provide sufficient inhibition of the mutant KIT to effect a significant therapeutic benefit. Generally, mutant KIT that is resistant to imatinib has an in vitro IC50 of the mutant KIT greater than about 3 micromolar. Imatinib resistant KIT mutations include D816F, D816H, D816N, D816Y, D816V, T670I and mutant forms that include V654A.
The selection of a compound that inhibits the mutant form of KIT is based on testing the compound or a number of compounds for their ability to inhibit the mutant KIT. Such testing is carried out by standard inhibition assays that are known in the art or within the skill of the artisan.
The KIT inhibitors utilized in accordance with the present method include midostaurin, vatalanib and compound A. Midostaurin (US5;093,330) and vatalanib (WO 98/35958) are known in the art. Compound A is a compound of the formula
Figure imgf000004_0001
And may be produced according to WO 04/005281. Appropriate dosages of midostaurin, vatanalib and compound A are determined by routine methods.
An appropriate dose of midostaurin is administered, e.g., once, twice or three times a day, for a total dose of 25 - 300 preferably 50-300 more preferably 50 -100 most preferably 100-300 mg daily, e.g., two or three times a day, for a total dose of 150-250 mg, preferably 225 mg daily.
An appropriate daily dose of vatanalib is an amount in the range from 300-4000 mg, e.g., in the range from 300-2000 mg/day or 300-1500 mg/day, in particular, 300, 500, 750, 1000, 1250, 1500 or 2000 mg/day, particularly 1250 mg/day.
The daily dose of compound A for a 70 kg/person is from approximately 0.05-5 g, preferably from approximately 0.25-1.5 g.
EXAMPLES
The human KIT gene encoding aa 544-976 was cloned into the baculovirus donor plasmid pFB-GST-01. This coding sequence was excised using restriction endonucleases Bam H1 and EcoRI and ligated to a Bac-to-Bac donor vector pFB-GEX-P1 with compatible ends. Subsequently the desired mutations were brought into the KIT gene by methods know to a person skilled in the art. Due to a frame shift within the original plasmid that was used to generate the mutant coding sequences, the mutated plasmid inserts were excised and inserted into the Bac-to-Bac donor vector pFB-GST-01 using the restriction enzymes BamH1-EcoR1 for each mutant shown in Figure 1. Automated sequencing confirmed the correct sequence to be present for each mutant plasmid.
Bacmid DNA was generated from 10 colonies each of DHIOBac cells transformed with pFB-GO1-KIT-mutant plasmid clones as described in materials and methods and these transfected into Sf9 cells. The transfected cells were pelleted and the resultant recombinant baculovirus present in the supernatant medium amplified. Western blotting was applied to the lysed cell pellets to confirm the expression of the GST-c-KIT fusion protein by the viral clones using anti-KIT and anti-GST antibodies for immonudetection.
pPH
Figure imgf000006_0001
D816Y D816F D816H Del557-561+V654A
Figure 1
Figure imgf000006_0002
average N° of HiS preparation IC50 μM SEM values HT-KIT-TA23 wt 1.7 0.15 2 HT-K1T TA23 -D820G 0.084 0.05 2 HT-K1T TA23 -T6701 0.89 0.21 2 average N° of GST preparation IC50 μM SEM values GST-KIT wt 1.8 0.26 10 GST-KIT Dei 557-561 0.32 0.042 3 GST-KIT Del 550-558 0.53 0.057 3 GST-KIT Dei 550-558÷ V654A 0.27 0.079 5 GST-KiT Dei 557-561 + V654A 0.34 0.11 5 GST-KiT V654A 0.46 0.16 5 GST-KiT K642E 0.64 0.036 4 GST-KIT 634W 0.33 0.13 2 GST-KiT T670I - Dei 550-558 0.11 0.05 2 GST-KiT D816F 0.41 0.055 5 GST-KiT D816H 0.35 0.078 5 GST-KiT D818N 0.74 0.25 5 GST-KiT D816Y 0.29 0.11 9 GST-KiT D816V 0.25 0.039 3 GST-KiT D816H ÷ R634W 0.08 0.04 2 GST-KiT N822H 0.37 0.12 5 GST-KiT N822K 0.15 0.058 5 GST-KiT Y823D 0.13 0.0075 3
Assay conditions: 1 μM ATP, 5 μg / ml Poly-EY, 10 min incubation at ambient temperature Virus containing media was collected from the transfected cell culture and used for infection to increase its titer. Virus containing media obtained after two rounds of infection was used for large-scale protein expression. For large-scale protein expression 100 cm2 round tissue culture plates were seeded with 5 x 107 cells/plate and infected with 1 mL of virus-containing media (approximately 5 MOls). After 3 days, the cells were scraped off the plate and centrifuged at 500 rpm for 5 minutes. Cell pellets from 10-20, 100 cm2 plates, were re-suspended in 50 mL of ice-cold lysis buffer (25 mM Tris-HCI, pH 7.5, 2 mM EDTA, 1 % NP-40, 1 mM DTT, 1 mM PMSF). The cells were stirred on ice for 15 minutes and then centrifuged at 5000 rpm for 20 minutes.
The centrifuged cell lysate was loaded onto a 2 mL glutathione-sepharose column (Pharmacia) and washed 3 x with 10 mL of 25 mM Tris-HCI, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCI. The GST-tagged proteins were then eluted by 10 applications (1 mL each) of 25 mM Tris-HCI, pH 7.5, 10 mM reduced-glutathione, 100 mM NaCI, 1 mM DTT, 10% glycerol and stored at -70°C.
The protein kinase activities of the various Kit mutants 200-500 ng were assayed in the presence or absence of inhibitors, 20 mM Tris-HCI, pH 7.6, 3 mM MnCI2, 3 mM MgCI2, 1 mM DTT, 10 μM Na3VO4, 3 μg/mL poly(Glu.Tyr) 4:1 , 1% DMSO, 1.5 μM ATP (γ-[33P]-ATP 0.1 μCi). The assay (30 μL) was carried out in 96-well plates at ambient temperature for 30 minutes and the reaction terminated by the addition of 20 μL of 125 mM EDTA. Subsequently, 30 μl of the reaction mixture were transferred onto Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5% H3PO4 and mounted on vacuum manifold with disconnected vacuum source. After spotting all samples, vacuum was connected and each well rinsed with 200 μL 0.5% H3PO . Membranes were removed and washed 4 x on a shaker with 1.0% H3PO4, once with ethanol. Membranes were counted after drying at ambient temperature, mounting in Packard TopCount 96-well frame, and addition of 10 μL/well of Microscint (Packard). IC50 values were calculated by linear regression analysis of the percentage inhibition of each compound in duplicate, at 4 concentrations (usually 0.01 , 0.1 , 1 and 10 μM). One unit of protein kinase activity is defined as 1 nmole of 33P transferred from [γ33P]ATP to the substrate protein/minute/mg of protein at RT.

Claims

We claim:
1. A method of treating a KIT dependent disease in a patient, which comprises: (a) identifying a mutant form of KIT associated with the KIT dependent disease; and (b) administering to said patient an effective mutant KIT inhibiting amount of an inhibitor selected from the group consisting of midostaurin, vatalanib and compound A.
2. A method of Claim 1 , wherein the mutant form of KIT is selected from D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561 , N822K, V654A, N822H, Del 550-558 + V654A, Del 557-561 + V654A, lns503AY, V560G, 558NP, Del 557- 558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I.
3. A method of Claim 2, wherein the mutant form of KIT is selected from D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561 , N822K, V654A, N822H, Del 550-558 + V654A, Del 557-561 + V654A.
4. A method of Claim 1, wherein the KIT dependent disease is resistant to treatment with imatinib.
5. A method of Claim 3, wherein the mutant form of KIT is D816F and the inhibitor is selected from the group consisting of midostaurin.
6. A method of Claim 3, wherein the mutant form of KIT is D816H and the inhibitor is selected from the group consisting of midostaurin.
7. A method of Claim 3, wherein the mutant form of KIT is D816N and the inhibitor is selected from the group consisting of midostaurin and compound A.
8. A method of Claim 3, wherein the mutant form of KIT is D816Y and the inhibitor is selected from the group consisting of midostaurin.
9. A method of Claim 3, wherein the mutant form of KIT is D816V and the inhibitor is selected from the group consisting of midostaurin.
10. A method of Claim 3, wherein the mutant form of KIT is K642E and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
11. A method of Claim 3, wherein the mutant form of KIT is Y823D and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
12. A method of Claim 3, wherein the mutant form of KIT is Del 550-558 and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
13. A method of Claim 3, wherein the mutant form of KIT is Del 557-561 and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
14. A method of Claim 3, wherein the mutant form of KIT is N822K and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
15. A method of Claim 3, wherein the mutant form of KIT is V654A and the inhibitor is selected from the group consisting of midostaurin.
16. A method of Claim 3, wherein the mutant form of KIT is N822H and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
17. A method of Claim 3, wherein the mutant form of KIT is Del 550-558 + V654A and the inhibitor is selected from the group consisting of midostaurin, vatalanib and compound A.
18. A method of Claim 3, wherein the mutant form of KIT is Del 557-561 + V654A and the inhibitor is selected from the group consisting of midostaurin.
19. A method of Claim 2, wherein the mutant form of KIT is selected from the group consisting of D816H, D816F, D816N and D816Y and the inhibitor is midostaurin.
20. A method of Claim 2, wherein the mutant form of KIT is selected from the group consisting of D816V, K642E, Y823D, Del550-558, Del 557-561, N822K, V654A, N822H, Del 550-558 + V654A, and Del 557-561 + V654A and the inhibitor is midostaurin.
21. A method of Claim 2, wherein the mutant form of KIT is selected from the group consisting of K642E, Y823D, Del 550-558, Del 557-561 , N822K and N822H and the inhibitor is vatalanib.
22. A method of Claim 2, wherein the mutant form of KIT is selected from the group consisting of D816H, D816N, K642E, Y823D, Del 550-558, Del 557-561 , N822K and N822H and the inhibitor is compound A.
23. A method according to any of Claims 1-22, wherein the KIT dependent disease is selected from mast cell diseases, acute myelogenous leukemia, gastrointestinal stromal tumors, seminomas and dysgerminomas.
24. A method of Claim 4, wherein the inhibitor is midostaurin.
25. A method of Claim 4, wherein the inhibitor is vatalanib.
26. A method of Claim 4, wherein the inhibitor is compound A.
PCT/EP2004/013045 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit WO2005049032A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
EP04818795A EP1686997B1 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
MXPA06005598A MXPA06005598A (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit.
DK04818795T DK1686997T3 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of KIT
SI200431159T SI1686997T1 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
PL04818795T PL1686997T3 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
CA2546189A CA2546189C (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
US10/579,586 US8017621B2 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
BRPI0416680-9A BRPI0416680A (en) 2003-11-18 2004-11-17 mutant form inhibitors
AT04818795T ATE428426T1 (en) 2003-11-18 2004-11-17 INHIBITOR OF THE MUTANT FORM OF KIT
NZ547195A NZ547195A (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
AU2004290902A AU2004290902B2 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
DE602004020654T DE602004020654D1 (en) 2003-11-18 2004-11-17 HAMMER OF THE MUTANT FORM OF KIT
JP2006540309A JP4762150B2 (en) 2003-11-18 2004-11-17 KIT mutant inhibitors
KR1020067009584A KR101153647B1 (en) 2003-11-18 2004-11-17 Inhibitors of the mutant form of kit
IL175578A IL175578A (en) 2003-11-18 2006-05-11 Use of a kit inhibitor for the manufacture of drugs for treating kit dependent diseases associated with a mutant form of kit
TNP2006000138A TNSN06138A1 (en) 2003-11-18 2006-05-15 INHIBITORS OF THE MUTANT FORM OF KIT
NO20062694A NO20062694L (en) 2003-11-18 2006-06-12 Inhibitor of mutant form of KIT
HK07100148.4A HK1093680A1 (en) 2003-11-18 2007-01-04 Inhibitors of the mutant form of kit kit
HR20090390T HRP20090390T1 (en) 2003-11-18 2009-07-08 Inhibitors of the mutant form of kit
US12/700,106 US8124611B2 (en) 2003-11-18 2010-02-04 Inhibitors of the mutant form of kit
US13/357,972 US20120157441A1 (en) 2003-11-18 2012-01-25 Inhibitors of the mutant form of kit
IL229124A IL229124A0 (en) 2003-11-18 2013-10-28 Inhibitors of the mutant form of kit

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US8673930B2 (en) 2005-05-02 2014-03-18 Novartis Ag Pyrimidylaminobenzamide derivatives for systemic mastocytosis
WO2006119154A1 (en) 2005-05-02 2006-11-09 Novartis Ag Use of pyrimidylamimobenzamide derivatives for the treatment of systematic mastocytosis
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US8017621B2 (en) 2011-09-13
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MXPA06005598A (en) 2006-08-11
CN101693031A (en) 2010-04-14
RU2405553C1 (en) 2010-12-10
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CA2546189A1 (en) 2005-06-02
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RU2009110449A (en) 2010-09-27
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NZ547195A (en) 2010-06-25
HK1093680A1 (en) 2007-03-09
CN102274230B (en) 2015-07-01
PT1686997E (en) 2009-07-17
RU2362562C2 (en) 2009-07-27
ATE428426T1 (en) 2009-05-15
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EP1686997B1 (en) 2009-04-15
CY1110354T1 (en) 2015-04-29
US20120157441A1 (en) 2012-06-21
PL1686997T3 (en) 2009-09-30
CN1882344A (en) 2006-12-20
RU2006121447A (en) 2008-01-10
EP1917965A1 (en) 2008-05-07
US20070213317A1 (en) 2007-09-13

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