Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

Fruit, Corinne; Couly, Florence; Bhansali, Rahul S.; Rammohan, Malini; Lindberg, Mattias F.; Crispino, John D.; Meijer, Laurent; Besson, Thierry

doi:10.3390/ph12040185

Cited by 11 publications

(14 citation statements)

References 46 publications

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“…After long-term treatment of FC162, a decreased G0 cell population was observed. Thus, these data reveal that FC162 phenocopies the effect of Dyrk1a genetic deletion [158]. Moreover, the following compound from this group-10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194) [155] also indicated an in vitro activity against DYRK1A with IC 50 = 6 nM and considerable selectivity in comparison to DYRK1B and CLK1.…”

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 72%

“…4-chlorocyclohepta[b]indol-10(5H)-one was identified as a novel dual DYRK1A/CLK1 inhibitor with slightly better solubility. X-ray structure analysis confirmed the binding mode of this compound to DYRK1A, exploiting mainly shape complementarity for tight-binding (Figure 22) [158]. In summary, inhibitors such as harmine, INDY, and leucine L41 have shown some promise in cellular assays due to their significant DYRK1A inhibitory activity.…”

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 73%

“…The results of kinase inhibition studies performed using proper bioassays have revealed that most of the tested compounds, except Mannich base, act as DYRK1A inhibitors with micromolar or even sub-micromolar concentrations applied. Compared to KuFal194, these novel compounds were less active and non-selective towards CLK1 [158]. 4-chlorocyclohepta[b]indol-10(5H)-one was identified as a novel dual DYRK1A/CLK1 inhibitor with slightly better solubility.…”

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 98%

“…However, it indicates significantly lower potency with IC50 1.06-1.17 µM [156,157]. Another compound belonging to the DYRK1A inhibitor class and characterized by nanomolar IC50 values is 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f ]quinazolin-9(8H)-one (also called FC162, Figure 20) [158]. FC162 has emerged as the most promising candidate based on in vitro cell studies than well-characterized DYRK1A inhibitors (e.g., leucettine 41 and EHT1610).…”

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 99%

“…FC162 has emerged as the most promising candidate based on in vitro cell studies than well-characterized DYRK1A inhibitors (e.g., leucettine 41 and EHT1610). It was reported that FC162 could cross the BBB and is effective in Thr212 phosphorylation [158]. In further studies, the activity of FC162 on tau-4R cells (SH-SY5Y cells which overexpressing the four-repeat human tau isoform) was examined.…”

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 99%

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Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Pucelik

Barzowska

Dąbrowski

et al. 2021

IJMS

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Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

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Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 72%

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 73%

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 98%

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 99%

Section: Perha Pharmaceutics Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Pucelik

Barzowska

Dąbrowski

et al. 2021

IJMS

View full text Add to dashboard Cite

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Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects

AlNajjar

Gabr

ElHady

et al. 2022

European Journal of Medicinal Chemistry

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DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity

et al. 2020

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Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

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Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

Cited by 11 publications

References 46 publications

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects

DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity

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