- Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
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The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an ortho-fluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.
- Tsang, Jonathan E.,Urner, Lorenz M.,Kim, Gyudong,Chow, Kingsley,Baufeld, Lynn,Faull, Kym,Cloughesy, Timothy F.,Clark, Peter M.,Jung, Michael E.,Nathanson, David A.
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p. 1799 - 1809
(2020/11/09)
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- A compound for the treatment of tumor (by machine translation)
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Formula (I) indicated by the compound or its pharmaceutically acceptable salt, or solvate thereof: Wherein R1 Is selected from R2 , R3 Are independently selected from H, halogen, alkyl, Or R2 And R3 Connected with a carbon atom containing 1 - 2 heteroatoms 1 substituted or multi-substituted six-membered aromatic heterocycle; R4 , R5 , R6 Are respectively represents a benzene ring on the 0 - 3 substituted, R4 , R5 , R6 Are independently selected from H, halogen atom, C1 - 6 Alkyl, C1 - 6 Alkoxy, hydroxy, amino, carboxyl, nitro, CH3 O (CH2 )n CH2 O -, Wherein n is 1 - 6 of the integer. The present invention provides the compounds in the preparation of a medicament for the treatment of tumor in use. Compound of the present invention the potency is clear. (by machine translation)
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Paragraph 0153; 0156; 0158
(2018/11/22)
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- Application of novel compound in preparing medicine for treating tumor
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The invention discloses application of a compound as shown in the formula (I), a pharmaceutically acceptable salt or a solvent compound of the compound in preparing a medicine for treating tumor. In the formula, R1 is selected from formulae as shown in the description; R2 and R3 are respectively independently selected from H, halogen, alkyl and a formula as shown in the description; or R2 and R3 form a one-substituted or polysubstituted hexahydric aromatic heterocyclic ring with 1-2 heteroatoms together with carbon atoms connected with R2 and R3; R4, R5 and R6 respectively represent 0-3 substitution on a benzene ring; R4, R5 and R6 are respectively and independently selected from H, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, carboxyl, nitryl, CH3O(CH2)nCH2O- and a formula as shown in the description; and in the formula, n is an integer of 1-6. The compound disclosed by the invention is definite in medicinal effect when being used for treating tumor.
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Paragraph 0161; 0162; 0164-0166
(2018/12/02)
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- PHARMACEUTICAL COMPOUNDS TARGETED BY MIF AFFINITY-TETHERED MOIETIES
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There is disclosed a compound, a pharmaceutical composition and a method of treatment using a pharmaceutical composition comprising a tethering moiety that is capable of binding to a macrophage migration inhibitory factor (MIF) polypeptide, optionally linked to a linker moiety and further covalently bound to a drug moiety or imaging agent. More specifically, there is disclosed a genus of affinity-tethering moieties covalently bound to a drug moiety or imaging agent either directly or optionally via a linker moiety to covalently link the tethering moiety to a drug moiety. Without being bound by theory, the disclosed pharmaceutical compounds are targeted to cancer cells or immune cells via an affinity-tethering moiety that hitch-hikes to or into its target cell while bound to endogenous MIF.
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Page/Page column 85; 86
(2015/01/09)
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- Three-point variation of a gefinitib quinazoline core
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A versatile four-step process describing the controlled systematic variation of a key quinazoline core from one intermediate is highlighted.
- Harris, Craig S.,Hennequin, Laurent F.,Willerval, Olivier
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supporting information; experimental part
p. 1600 - 1602
(2009/06/18)
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