Substituted quinazolines for inhibiting kinase activity
Inventors
Qian, Xiangping • Zhu, Yong-Liang
Assignees
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Publication Number
US-10653701-B2
Publication Date
2020-05-19
Expiration Date
Abstract
Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.
Core Innovation
The invention relates to substituted quinazoline compounds that include an electrophilic group capable of forming a covalent bond with a nucleophile, or a pharmaceutically acceptable salt thereof. The disclosed chemistry centers on Formula I and related variants, including Formula Ia, Formula Ib, and Formula Ib or Formula Ib, and includes substituted quinazoline acrylamide compounds and related derivatives. The compounds are described as covalent inhibitors with broad substituent variability within the quinazoline scaffold.
The disclosure further relates to a method of treating cancer in a patient having one or more mutations in the EGFR gene by administering a therapeutically effective amount of a substituted quinazoline compound or a pharmaceutically acceptable salt thereof. The treated cancer is skin cancer or lung cancer. The text also identifies EGFR mutation variants and lists examples of electrophile-bearing quinazoline compounds, including acrylamide, but-2-enamide, methacrylamide, propiolamide, and ethenesulfonamide examples.
The document additionally describes pharmaceutical compositions comprising the substituted quinazoline compounds or pharmaceutically acceptable salts, together with routes of administration and other compound forms such as salts, N-oxides, stereoisomers, tautomers, polymorphs, solvates, chelates, and non-covalent complexes. Example compounds and characterization data are disclosed to support the described substituted quinazoline chemistry.
Claims Coverage
The consolidated claim coverage centers on an independent method of treating cancer in a patient having one or more EGFR gene mutations by administering a substituted quinazoline compound comprising an electrophilic group capable of forming a covalent bond with a nucleophile, where the cancer is skin cancer or lung cancer. The claim set adds five recurring inventive features: EGFR mutation selection, structural definition by Formula Ib or related formula language, enumerated acrylamide-substituted quinazoline derivatives, and unit-dose and daily dosage ranges.
Treating EGFR-mutated skin or lung cancer with covalent quinazoline
A method of treating cancer in a patient having one or more mutations in the EGFR gene by administering a therapeutically effective amount of a substituted quinazoline compound comprising an electrophilic group capable of forming a covalent bond with a nucleophile, or a pharmaceutically acceptable salt thereof, wherein the cancer is skin cancer or lung cancer.
EGFR mutation set selection
The method further specifies that the EGFR mutation is selected from a listed group of specific EGFR mutation variants.
Formula-based substituted quinazoline definition
The method uses a substituted quinazoline compound defined by Formula Ib or related structural formula language with specified substituent variables and an electrophilic group E.
Enumerated acrylamide-substituted quinazoline derivatives
The method uses a substituted quinazoline compound selected from a listed group of specific acrylamide-substituted quinazoline derivatives, including pharmaceutically acceptable salts thereof.
Unit-dose range
The method includes administering the substituted quinazoline compound in a unit dose ranging from about 1 mg to about 1000 mg.
Daily dosage range
The method includes administering the substituted quinazoline compound at a daily dosage ranging from about 0.01 mg/kg to about 100 mg/kg body weight.
Overall, the claim coverage is directed to administering substituted quinazoline compounds with electrophilic covalent-bond-forming groups for treating EGFR-mutated skin cancer or lung cancer, with dependent features narrowing the eligible EGFR mutations, compound structures, and dosing ranges.
Stated Advantages
Inhibits EGFR, including activating mutants and resistance-associated mutants such as L858R, T790M, del E746-A750, and L858R/T790M.
Provides in vitro binding activity with Kd ranges down to 31 nM.
Provides kinase inhibition potency with IC50 ranges down to 3100 nM or lower.
Provides cellular proliferation inhibition in EGFR-mutant tumor cell lines using IC50 criteria.
Reports xenograft tumor growth inhibition in an EGFR-mutant model.
Documented Applications
Treating skin cancer or lung cancer in patients having one or more mutations in the EGFR gene.
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