Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor

Zhang, Lingtian; Lakkaniga, Naga Rajiv; Bharate, Jaideep B.; McConnell, Nicholas; Wang, Xiuqi; Kharbanda, Anupreet; Leung, Yuet-Kin; Frett, Brendan; Shah, Neil P.; Li, Hongyu

doi:10.1016/j.ejmech.2021.113776

Cited by 11 publications

(5 citation statements)

References 28 publications

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“…Zhang et al synthesized and tested imidazo[1,2-a]pyridine thiophene compound inhibitors of FLT3 and its mutant forms [ 65 ]. Among the tested molecules, compound 5o was effective against MOLM-14 AML cells, even when manipulated to express the mutant FLT3-ITD D835Y or FLT3-ITD F691L forms.…”

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

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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.

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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

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“…In vitro studies using cell lines and xenograft models have validated their efficacy. Below, we have selected several studies [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] that have identified novel FLT3i with interesting efficacy and selectivity data, probably leading actors in future clinical trials. Table 3 summarizes the preclinical studies analyzing new compounds with their sensitivities and resistances.…”

Section: Flt3i: Indications Mechanisms Of Resistance In Vitro and In ...mentioning

confidence: 99%

“…New FLT3i have shown interesting activity against mutations which confer resistance, such as Compounds 17, 8r, 5o [ 70 , 71 , 72 ], but current molecular studies, investigating resistance in FLT3mut AML patients, relapsing after treatment, suggest that the persistence or the selection of one or more subclones, are the natural evolution of target inhibition, and that combination with other agents, with different mechanisms of action, is necessary to overcome resistance. The R/R setting still remains an unmet medical need, because of the high relapse rate observed even after HSCT.…”

Section: Flt3i: the Past The Present The Futurementioning

confidence: 99%

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Capelli

Menotti

Fiorentini

et al. 2022

Cancers

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FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

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“…Thus, the bioisosteres of adenine serve as hinge-binders in kinase inhibitors. 7 Several bicyclic heterocycles have been successfully explored as hinge binders, including quinazoline, 8 pyrrolopyrimidines, 9 quinoline, imidazopyridines 10 and pyrazolopyridines. 11 Pyrazolopyridine is a privileged scaffold in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

“…Several pyrazolopyridine derivatives have been identified as the inhibitors of various kinases, demonstrating the growing influence of pyrazolopyridine-based kinase inhibitors in anticancer drug discovery. Recently, the RET kinase inhibitor selpercatinib (10) bearing a pyrazolo[1,5-a]pyridine core was approved for the treatment of non-small cell lung cancer (NSCLC) and thyroid cancer (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy

Halder,

Rai,

Talukdar

et al. 2024

RSC Med. Chem.

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Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor

Cited by 11 publications

References 28 publications

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

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

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy

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