BIOMAT Database Logo BIOMAT Database Logo

Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations. 2021

Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia.

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000588 Amines A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed) Amine
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D001372 Aza Compounds Organic chemicals where carbon atoms have been replaced by nitrogen atoms. Compounds, Aza
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured

Related Publications

Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors.
November 2020, Molecules (Basel, Switzerland),
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of N-(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors.
August 2023, ACS medicinal chemistry letters,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia.
July 2022, European journal of medicinal chemistry,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.
April 2023, Drug development research,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors.
November 2021, European journal of medicinal chemistry,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of quinolinone derivatives as potent FLT3 inhibitors.
March 2014, Biochemical and biophysical research communications,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11.
July 2018, Bioorganic & medicinal chemistry letters,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer.
December 2020, European journal of medicinal chemistry,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia.
June 2020, European journal of medicinal chemistry,
Yi Long, and Mingfeng Yu, and Aleksandra M Ochnik, and Jasmine D Karanjia, and Sunita Kc Basnet, and Alemwork A Kebede, and Lianmeng Kou, and Shudong Wang
Discovery of benzimidazole-indazole derivatives as potent FLT3-tyrosine kinase domain mutant kinase inhibitors for acute myeloid leukemia.
December 2023, European journal of medicinal chemistry,
Copied contents to your clipboard!