153 results about "Egfr mutation" patented technology

The present invention relates to mutations in Epidermal Growth Factor Receptor (EGFR) and methods of detecting such mutations as well as prognostic methods method for identifying a tumors that are susceptible to anticancer therapy such as chemotherapy and / or kinase inhibitor treatment. The methods involve determining the presence of a mutated EGFR gene or mutated EGFR protein in a tumor sample whereby the presence of a mutated EGFR gene or protein indicates the tumor is susceptible to treatment.

The invention relates to a clustered regularly interspaced short palindromic repeats (CRISPR) / Cas guide RNA (gRNA) comprising a targeting domain that is complementary to human genomic Epidermal Growth Factor Receptor (EGFR) DNA, and a vector system including one or more packaged vector(s) including: (a) a first regulatory element operably linked to a gRNA, and (b) a second regulatory element operably linked to a nucleic acid encoding a Cas protein. Also disclosed are methods of altering a nucleic acid sequence encoding EGFR in a cell including contacting the cell with a vector system, methods of treating lung cancer, and methods of selectively inducing apoptosis in a cell including administering a gRNA to the cell.

The present invention relates to the treatment of EGFR-mediated disease, particularly cancer, which is resistant to tyrosine kinase inhibitor therapies. Methods for treatment of cancer and reduction of tumor growth in individuals with secondary EGFR mutations, particularly tyrosine kinase domain mutations, resistant to standard therapy are provided. The invention provides methods for the treatment of tyrosine kinase inhibitor resistant cancers with anti-EGFR antibodies. Methods for treatment of recurrent lung cancer, including non-small cell lung carcinoma which is resistant to tyrosine kinase inhibitors, with the antibody anti-EGFR mAb806 are described.

The present invention relates to a method of treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour, for instance an activating mutation of the EGFR or a mutation responsible for resistance or the emergence of acquired resistance to treatment with reversible EGFR and / or HER2 inhibitors or irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357, comprising administering an effective amount of the irreversible EGFR inhibitor BIBW2992 (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, to a person in need of such treatment, optionally in combination with the administration of a further chemotherapeutic agent, in combination with radiotherapy, radio-immunotherapy and / or tumour resection by surgery, and to the use of a BIBW 2992 (1) for preparing a pharmaceutical composition for the treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour.

Disclosed are biomarkers, methods and assay kits for the identification of cancer patients who are predicted to benefit, or not to benefit, from the therapeutic administration of an epidermal growth factor receptor (EGFR) inhibitor. The biomarkers of the present invention include detection of EGFR and HER 2 gene amplification and polysomy, EGFR protein expression, EGFR mutations, phosphorylated Akt protein expression, and various combinations of such biomarkers, as well as the combination of these biomarkers with mutations in the tyrosine kinase domain of the EGFR gene. Increased EGFR gene copy number, increased HER2 gene copy number, increased EGFR, protein expression, activated AKT protein expression (phosphorylated AKT) and EGFR mutations are all associated with better outcome for cancer patients treated with EGFR inhibitors. The invention provides a diagnostic paradigm based on each of these tests and combinations of these tests to select cancer patients who will benefit from EGFR inhibitor therapy, as well as a diagnostic paradigm to select cancer patients who will not benefit from EGFR inhibitor therapy.

The invention features a method for treating patients who have an EGFR-driven cancer, which is, or has become, refractory to a tyrosine kinase inhibitor, such as eriotinib and gefitinib, by administering a compound of formula (I) to the patient. The invention also features treating EGFR-driven cancers having an EGFR mutation identified herein.

Polymerase chain reaction primers and methods directed to detecting the EGFR mutant C→T at the position corresponding to base 2369 of EGFR cDNA. The invention provides a PCR primer that hybridizes under suitable PCR conditions to a polynucleotide sequence 5′ in each respective strand to a mutation of an EGFR gene that encodes a substitution of threonine by methionine at position 790 of the EGFR polypeptide. The invention also provides a PCR primer hybridizes to a sequence that includes a mutant T at the position corresponding to base 2369 of EGFR cDNA but not to a second EGFR polynucleotide containing a wild type C. The invention provides several methods and kits for detecting a mutant epidermal growth factor receptor (EGFR) gene in a sample comprising probing the sample with a means for selectively detecting a nucleotide sequence comprising a mutant T at the position corresponding to base 2369 of EGFR cDNA, and identifying that the base at said position is T. These methods and kits are also useful to predict resistance to the therapeutic effects of gefitinib or erlotinib in a subject suffering from or suspected of having a cancer.

The present invention refers to the detection of EGFR mutations in a blood (serum / plasma) sample from a subject. The method comprises: (i) obtaining the DNA from said sample; (ii) amplifying the nucleic acid sequence corresponding to a specific region of the EGFR gene by means of PCR using a Protein-Nucleic Acid probe; 10 and (iii) detecting said mutation.

A synergistically effective combination of an anti-cancer agent and a therapeutic compound, such as an mTOR-Rictor complex inhibitor, a Serine 473 phosphorylation inhibitor, an AKT2 inhibitor, or a combination thereof, for use in the treatment of cancer, and methods and uses thereof. Also included are methods and uses of a thiosemicarbazone for treating a cancer in a mammal in need thereof characterized by over-expression of RAS, by an EGFR mutation, and / or by over-expression of AKT2.

Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and / or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative,and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.

The invention discloses a nitrogen-containing heterogeneous ring compound, a preparation method thereof and an application of the nitrogen-containing heterogeneous ring compound in inhibition of kinase activity. The general formula of the nitrogen-containing heterogeneous ring compound is represented as a formula I or a formula I', wherein R1, R2, R3 and R4 in the formula I or the formula I' are selected from any one of hydrogen, halogen, cyanogroup, hydroxyl, amidogen and substituted or unsubstituted C1-C6 alkyl groups independently, and a 3-10-membered ring system can be formed by any two groups in R1, R2, R3 and R4; M1, M2 and M3 are selected from CRa or N independently, and at least one of M1, M2 and M3 is N; W is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or halogenated 4-8-membered alkine groups, substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 4-8-membered heterocyclic groups, 5-10-membered aromatic or heteroaryl groups, substituted carbonyl, substituted sulfonyl and substituted or unsubstituted amidogen. The nitrogen-containing heterogeneous ring compound can inhibit EGFR (epidermal growth factor receptor) mutant kinase activity or ALK (anaplastic lymphoma kinase) activity and is a multi-target tumor therapeutic drug with a brand-new action mechanism.

The present invention relates to mutations in Epidermal Growth Factor Receptor (EGFR) and methods of detecting such mutations as well as prognostic methods method for identifying a tumors that are susceptible to anticancer therapy such as chemotherapy and / or kinase inhibitor treatment. The methods involve determining the presence of a mutated EGFR gene or mutated EGFR protein in a tumor sample whereby the presence of a mutated EGFR gene or protein indicates the tumor is susceptible to treatment.

The present invention provides a new group of protein kinase inhibitors, aminopyrimidine derivatives, and pharmaceutically acceptable salts thereof that are useful for treating cell proliferative disease and disorder such as cancer and immune disease. The present invention provides methods for synthesizing and administering the protein kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefore. The invention also provides useful intermediates generated during the syntheses of the aminopyrimidine derivatives.

The invention discloses a pyrimidine compound, an EGFR inhibitor and application of the EGFR inhibitor. The pyrimidine compound is prepared from a compound shown in the formula I or pharmaceutically acceptable salt thereof, a stereoisomer, and a solvate or prodrug. The EGFR inhibitor contains the pyrimidine compound. The pyrimidine compound can inhibit activated or resistant mutation of one or more kinds of EGFRs, can inhibit proliferation of the EGFR T790M / L858R double-mutant enzyme in the nanomolar concentration, but has a weak inhibiting effect on the wild EGFR enzyme; the pyrimidine compound is applicable to treatment of the EGFR-sensitive mutations cancer and also suitable for cases with secondary dug resistance in present EGFR-TKI treatment; meanwhile, toxic and side effects caused by inhibition on the wild EGFR are greatly reduced due to the mutation selectivity of the pyrimidine compound, and the pyrimidine compound is an ideal treatment drug for diseases caused by EGFR mutation.

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a class of phenyl substituted triazine compounds having epidermal growth factor receptor inhibition effects, a pharmaceutical composition containing the compound, and uses of the compounds or the pharmaceutical composition as cancer treatment drugs. According to the present invention, the compounds have good inhibition activity on mutant EGFR kinase, exhibit excellent selectivity, and are expected to be the drugs providing specific treatment effects on drug resistance tumors, especially EGFR mutation-causing drug resistance tumors.

Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and / or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative, and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.

The invention discloses inhibitors with ALK and EGFR dual activity, and a preparation method and an application thereof, and relates to N-(3-((4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2-yl)amino)phenyl)acryloylamide analogs represented by formula (I), and stereoisomers or pharmaceutically acceptable salts thereof. The series of compounds have epidermal growth factor receptor (EGFR) L858R EGFR mutant, T790MEGFR mutant and exon 19 deleted active mutant inhibition activity, and also have ALK inhibition activity, so the series of compounds can be used to treat EGFR mutant and ALK activity individually or partially mediated diseases, can be widely applied to medicines for preventing and treating cancers and especially non-small cell lung cancers, and is hopeful to be developed into new generation EGFR or / and ALK inhibitors.

The invention relates to a tricyclic compound of the formula (I) and the formula (II) and pharmaceutical acceptable salts of the tricyclic compound. The compounds of the kind can be applied to inhibit mutants, such as EGFR (L858R), EGFR (delE746-A750) and EGFR (T790M), of EGFR kinase, and can also be used for treating cancer, such as the non-small cell lung cancer, caused by the mutants of the EGFR. The invention further relates to pharmaceutical compositions containing the compounds of the kind, methods for preparing the compounds of the kind and application of the compounds of the kind or the pharmaceutical compositions for preparing medicines for treating the cancers caused by the mutants of the EGFR.

The present invention relates to a tricyclic compound of formula (I) and a pharmaceutically acceptable salt thereof. The compound can be used for inhibiting mutants of epidermal growth factor receptor(EGFR) kinases, such as EGFR (delE746-A750), EGFR (L858R), EGFR (delE746-A750 / T790M), EGFR (L858R / T790M), EGFR exon 20insertion and other mutants, so the compound can be used to treat cancer caused by EGFR mutants, such as non-small cell lung cancer. The invention also relates to a medicinal composition containing the compound, a method for preparing the compound, and an application of the compound or the medicinal composition in the preparation of medicines for treating the cancers caused by EGFR mutants.

The invention features a method for treating patients who have an EGFR-driven cancer, which is, or has become, refractory to a tyrosine kinase inhibitor, such as eriotinib and gefitinib, by administering a compound of formula (I) to the patient. The invention also features treating EGFR-driven cancers having an EGFR mutation identified herein.

The invention provides a microfluidic chip for instantly detecting EGFR (epidermal growth factor receptor) mutation. The microfluidic chip integrates the functions of nucleic acid extraction, LAMP (loop-mediated isothermal amplification) and instant detection. The microfluidic chip solves the problem of centrifugation step required by DNA (deoxyribonucleic acid) extraction before constant-temperature DNA amplification and the problem of thermal circulation apparatus required by DNA amplification, and conforms to the general requirements for diagnostic detection in underdeveloped regions provided by WHO (World Health Organization).

The invention discloses a miazines compound, an EGFR inhibitor and application thereof. The miazines compound comprises a compound shown as formula I, or pharmaceutically acceptable salt, stereisomer, solvate or prodrug thereof; and the EGFR inhibitor contains the miazines compound. The miazines compound disclosed by the invention can inhibit the activation or resistant mutation of one or more EGFRs; the multiplication of EGFRT790M / L858R amphimutation enzyme can be inhibited under nanomole concentration, and the inhibition for wild type EGFR enzyme is relatively weak; the miazines compound can be used for the treatment of EGFR sensitive mutation cancers, and is also applicable for cases generating secondary drug resistance in current EGFR-TKI treatment; and moreover, the mutation selectivity greatly reduces toxic and side effects generated by the inhibition of the wild type EGFR, and the miazines compound is an ideal therapeutic drug for diseases caused by EGFR mutation.

The invention provides a primer and probe assembly for detecting specific mutation on 18, 19, 20 and 21 exons of EGFR genes, a kit which comprises the primer and probe assembly and is used for detecting EGFR mutation sites through multiple droplet digital PCR as well as an application and a use method of the primer and probe assembly or the kit. The primer and probe assembly or the kit can performhigh-throughput detection on 29 mutation sites of the EGFR genes, has high specificity, high sensitivity and good stability, has great significance in mutation detection of EGFR genes of NSCLC (non-small cell lung cancer) and can dynamically guide medication for patients.

The invention discloses a circulating tumor DNA EGFR (Epidermal Growth Factor Receptor) detecting technology and a reagent kit thereof. The circulating tumor DNA EGFR detecting technology comprises the following steps: step 1, designing a synthetic primer, a closed probe and a detecting probe for a mutation site; step 2, processing a sample and extracting DNA; step 3, applying the circulating tumor DNA EGFR detecting technology to the reagent kit, and establishing a PCR amplified reaction system. According to the circulating tumor DNA EGFR detecting technology disclosed by the invention, the specific MGB Blocker probe, the EGFR specific probe and the primer are adopted to detect the EGFR mutation in the circulating tumor DNA; the MGB Blocker probe is utilized to retard nonspecific amplification of the EGFR wild type genome and improves the sensitivity; the circulating tumor DNA EGFR detecting technology can be used for detecting the EGFR mutation in the circulating tumor DNA, is simple to operate, cheap in detection, capable of being popularized at a large scale and high in detection speed; the detecting process can be completed for about 2 hours.

Mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies. We generated single chain variable fragments (scFvs) specific for mutant peptides presented on the cell surface by human leukocyte antigen (HLA) molecules. These scFvs can be converted to full-length antibodies, termed MANAbodies, targeting “Mutation Associated Neo-Antigens” bound to HLA. A phage display library representing a highly diverse array of single-chain variable fragment sequences was first designed and constructed. A competitive selection protocol was then used to identify clones specific for peptides bound to pre-defined HLA types. In this way, we obtained scFvs, including one specific for a peptide encoded by a common KRAS mutant and another by a common EGFR mutant. Molecules targeting MANA can be developed that specifically react with mutant peptide-HLA complexes even when these peptides differ by only one amino acid from the normal, wild-type form.

The invention discloses deuterated osimertinib derivatives shown as formula I in the description as well as pharmaceutically acceptable salts, stereisomers, solvates or prodrugs of the derivatives, wherein all symbols are defined in claims. The deuterated osimertinib derivatives can inhibit activation or resistant mutation of one or more EGFRs (epidermal growth factor receptors), can be used for treating EGFR sensitive mutation cancer and are ideal therapeutic drugs for treating EGFR mutation derived diseases.

The present invention relates to a method of treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour, for instance an activating mutation of the EGFR or a mutation responsible for resistance or the emergence of acquired resistance to treatment with reversible EGFR and / or HER2 inhibitors or irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357, comprising administering an effect ive amount of the irreversible EGFR inhibitor BIBW2992 (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, to a person in need of such treatment, optionally in combination with the administration of a further chemotherapeutic agent, in combination with radiotherapy, radio-immunotherapy and / or tumour resection by surgery, and to the use of a BIBW 2992 (1) for preparing a pharmaceutical composition for the treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour.

The invention belongs to the technical field of medical chemistry, and specifically relates to a novel epidermal growth factor receptor inhibitor, a pharmaceutical composition containing the novel epidermal growth factor receptor inhibitor and use of the novel epidermal growth factor receptor inhibitor or the pharmaceutical composition as a cancer prevention and / or treatment medicament. The compounds exhibit excellent EGFR (Epidermal Growth Factor Receptor) inhibition activity, especially for mutative EGFR, and is expected to become a pharmaceutical with a special treatment effect and smaller side effect on resisting pharmaceutical-resistant tumors caused by EGFR mutation.