Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

Baska, Ferenc; Sipos, Andrea; Őrfi, Zoltán; Nemes, Zoltán; Dobos, Judit; Szántai-Kis, Csaba; Szabó, Eszter; Szénási, Gábor; Dézsi, László; Hamar, Péter; Cserepes, Mihály; Tóvári, József; Garamvölgyi, Rita; Krekó, Marcell; Őrfi, László

doi:10.1016/j.ejmech.2019.111710

Cited by 11 publications

(4 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intermediates 9, 11 and 18 were already reported in ref. 28, while 10, [36] 12, [37] 13, [38] and 17 [36] had been already described but were obtained in different ways.…”

Section: Chemistrymentioning

confidence: 92%

“…The organic layer was washed twice with water and brine, dried over Na 2 SO 4 , and concentrated under vacuum, to afford the proper 4-chloroquinazoline as a solid. [36] Starting from 10 (0.24 g, 0.71 mmol) and SOCl 2 (0.50 mL, 7.10 mmol) in 10.0 mL of CHCl 3 (free of ethanol), compound 17 (0.23 g, yield: 91.8 %) was obtained as a yellow solid.…”

Section: General Procedures For the Synthesis Of 4-chloroquinazolines...mentioning

confidence: 99%

“…28. [36] Following the procedure described in ref. 28, starting from 8 (0.46 g, 1.36 mmol) and 33.0 % ammonia water (3.0 mL) in 7.0 mL of abs.…”

Section: -(345-trimethoxyphenyl)-4h-benzo[d][13]oxazin-4-one (9)mentioning

confidence: 99%

See 2 more Smart Citations

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

et al. 2022

View full text Add to dashboard Cite

Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC 50 values in the nanomolar range (1 d, 1 e, 2 a, 2 c, 2 e). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.

show abstract

“…Intermediates 9, 11 and 18 were already reported in ref. 28, while 10, [36] 12, [37] 13, [38] and 17 [36] had been already described but were obtained in different ways.…”

Section: Chemistrymentioning

confidence: 92%

Section: General Procedures For the Synthesis Of 4-chloroquinazolines...mentioning

confidence: 99%

See 1 more Smart Citation

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Promising results have been achieved with phenylethenylquinazoline derivatives in terms of selectivity [ 62 ]. They inhibited the activity of FLT3-ITD, FLT3 D835Y and the quizartinib-resistant FLT3-ITD D835Y double-mutant enzyme while exerting almost no effect over c-KIT.…”

Section: Novel Molecules Targeting Proliferative Mechanisms In Acute ...mentioning

confidence: 99%

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

et al. 2023

View full text Add to dashboard Cite

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kd, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

show abstract

Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells

Cui

Zhu

et al. 2021

Bioorganic Chemistry

View full text Add to dashboard Cite

Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

Cited by 11 publications

References 53 publications

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells

Contact Info

Product

Resources

About