Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation

Kumar, Kunal; Wang, Peng; Swartz, Ethan; Khamrui, Susmita; Secor, Cody; Lazarus, Michael B.; Sánchez, Roberto; Stewart, Andrew F.; DeVita, Robert J.

doi:10.3390/molecules25081983

Cited by 14 publications

(18 citation statements)

References 53 publications

(53 reference statements)

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“…Even though endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass and actually cure diabetes, the known chemical compounds that promote regeneration or expansion of endogenous β-cells still have inadequate potency for clinical application. Up to date, several β-cell replication-promoting compounds were investigated, including harmine and its analogs [ 5 , 6 , 7 , 8 , 9 , 10 ], leucettines [ 11 , 12 ], CC-401 [ 13 ], 5-iodotubercidin (5-IT) [ 14 ], INDY [ 15 ] and benzothiazoles derivatives [ 16 ], azaindoles and aminopyrazines such as GNF-4877 [ 17 , 18 , 19 ], VBIT-4, G-1 [ 3 , 4 ] ( Figure S1 ). The common feature of these agents is that they act through inhibition of a dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) [ 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Barzowska

Pucelik

Pustelny

et al. 2021

Cells

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The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

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Section: Introductionmentioning

confidence: 99%

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Barzowska

Pucelik

Pustelny

et al. 2021

Cells

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“…Structure-based drug design and development were used to identify kinome and CNS off-targets and harmine-like molecules for more specific therapy. The crystal structure of DYRK1A with ATP-binding inhibitor DJM2005, 1, 7, and 9-amino harmine analogs were synthesized and examined in terms of their effect on DYRK1A binding and β-cell proliferation (Figure 11andFigure 12) [15,147,148]. Harmine analogs with polar substituents, e.g., hydroxymethyl or -acetyl, at position 1-C (Figure 12), showed good DYRK1A inhibition (IC50 49-67 nM).…”

Section: Harmine and Its Analogues-sar Approachmentioning

confidence: 99%

“…In the subsequent paper, the same authors reported the set of harmine derivatives modified in 7-position as DYRK1A inhibitors with activity on human β-cell proliferation and targeted drug delivery [147]. The harmine backbone was substituted by terminal methyl ester, carboxamide, carboxylic acid, and amino/substituted amino groups with various carbon (1-5) chain lengths.…”

Section: Harmine and Its Analogues-sar Approachmentioning

confidence: 99%

“…These compounds indicated an increase in β-cell proliferation (3-fold less than harmine). The reduced (in comparison to harmine) efficacy of described 7-O derivatives may be caused by several structural and biological factors, including lower potency for DYRK1A inhibition, limited cell permeability, reduced DYRK1A targeting and/or off-target kinase activity [147]. 9-N-substituted analogues of harmine were also studied in order to eliminate the disadvantages of kinase and off-target [148].…”

Section: Harmine and Its Analogues-sar Approachmentioning

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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“…They can improve benign prostatic hypertrophy symptoms (23) and the immune system (24). B-carboline alkaloids increase the growth and differentiation of bone and cartilage cells in cells and rats (25,26). Nonetheless, more studies are needed in this regard since no study has so far focused on osteoporosis in menopausal women.…”

Section: Introductionmentioning

confidence: 99%

Effect of oral capsule of Peganum harmala seeds on bone density in menopausal women prone to osteoporosis

Hafshejani

Lorigooini

Deris

et al. 2021

J Shahrekord Univ Med Sci

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Background and aims: Osteoporosis is one of the most common metabolic bone diseases with systemic involvement of the body skeleton. The Peganum harmala seed contains high amounts of carboline alkaloids, which have been shown to have positive effects on bone formation in animal studies. In the present study, the effect of an oral capsule of P. harmala seed on bone density was evaluated in menopausal women prone to osteoporosis. Methods: In this randomized controlled clinical trial, 100 women referring to the orthopedic clinic with a diagnosis of osteoporosis were included and divided into the intervention group treated with calcium D (500 mg) twice a day, Osteofos (70 mg) per week, and P. harmala (500 mg) twice‐a‐day, and the control group treated with calcium D and Osteofos. Before and three months after the intervention, patients were evaluated for osteoporosis using bone densitometry. Finally, independent t-test, paired t-test, and repeated measures ANOVA were used for statistical analysis. Results: The mean bone mineral density (BMD) of the femur before and after the intervention showed significant improvements in the intervention and control groups (P<0.001). The mean differences in BMD before and after the intervention were significant in both control and intervention groups with higher improvements in the intervention group (P<0.001). Although the mean BMD of the spine before the intervention was not significantly different between the two groups (P=0.167), it was better in the intervention group after the intervention (P=0.030). Conclusion: The findings of the present study confirmed the beneficial effects of P. harmala on osteoporosis while the lack of any changes in liver enzymes.

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Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation

Cited by 14 publications

References 53 publications

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

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

Effect of oral capsule of Peganum harmala seeds on bone density in menopausal women prone to osteoporosis

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