Topical advances in PIM kinases and their inhibitors: Medicinal chemistry perspectives

Walhekar, Vinayak; Bagul, Chandrakant; Kumar, Dileep; Muthal, Amol P.; Garlapati, Achaiah; Kulkarni, Ravindra

doi:10.1016/j.bbcan.2022.188725

Cited by 19 publications

(12 citation statements)

References 110 publications

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“…PIM-1 is localized on chromosome 6p21, PIM-2 on chromosome Xp11. 23, and PIM-3 on chromosome 22q13. 22 In contrast to conventional serine/threonine kinases, the PIM family possesses a unique characteristic in their interaction with ATP or competitive inhibitors of ATP.…”

Section: Structures and Biological Functions Of Pimmentioning

confidence: 99%

“…They exhibit constitutive activity, and their phosphorylation mechanism primarily serves to enhance enzyme stability rather than directly regulate catalytic activity. 23 It is well-known that the development of targeted drugs has been a particularly important aspect of oncology drug therapy, and the unique properties of PIM kinase allow the design and discovery of compounds that specifically target PIM kinase without interfering with the regulatory mechanisms of other kinases, potentially leading to more effective and specific therapeutic interventions. 24 The PIM kinase family is characterized by a high degree of sequence similarity in its genetic composition, e.g., PIM-2 kinase shares 55% homology with PIM-1, whereas PIM-3 was initially named depolarisation-inducible kinase (KID-1), which was renamed PIM-3 precisely because of the 71% amino acid level identity with PIM-1 and 44.0% identity with PIM-2 (Figure 1A).…”

Section: Structures and Biological Functions Of Pimmentioning

confidence: 99%

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Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Chen,

Mao,

Ren

et al. 2024

J. Med. Chem.

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Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine kinases consisting of three members, PIM-1, PIM-2, and PIM-3. These kinases regulate a wide range of substrates through phosphorylation and affect key cellular processes such as transcription, translation, proliferation, apoptosis, and energy metabolism. Several PIM inhibitors are currently undergoing clinical trials, such as a phase I clinical trial of Uzanserti (5) for the treatment of relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses the structural and biological characterization of PIM, ongoing research progress on small-molecule inhibitors undergoing clinical trials, and evaluation analysis of persisting challenges in this field. Additionally, the design and discovery of small-molecule inhibitors targeting PIM in recent years have been explored, with a particular emphasis on medicinal chemistry, aiming to provide valuable insights for the future development of PIM inhibitors. ■ SIGNIFICANCEA concise summary of research in the field of PIM inhibition for cancer, with a focus on medicinal chemistry, is presented. An analysis of current compounds entering clinical trials highlights existing issues and provides viewpoints on potential solutions. Future prospects and recommendations for development are discussed, emphasizing the need for unique perspectives and analyses in medicinal chemistry to stimulate critical thinking, expand understanding, and advance research in this field.

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Section: Structures and Biological Functions Of Pimmentioning

confidence: 99%

Section: Structures and Biological Functions Of Pimmentioning

confidence: 99%

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Chen,

Mao,

Ren

et al. 2024

J. Med. Chem.

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“…In addition, it is involved in many biological processes such as cell cycle, cell proliferation, apoptosis, and drug resistance 10 . PIM-1 kinase has unusual adenosine triphosphate (ATP) binding pocket having proline 123 in the hinge region which is specific to PIM-1 kinase over other serine/threonine kinases 11 . Therefore, ATP could not bind to the hinge region by a second hydrogen bond as other protein kinases 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

El-Miligy

Abdelaziz

Fahmy

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b , 5c , 6e, 13a , 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b , 5c , 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases.

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“…The Pim kinase family of serine/threonine kinases consists of three members (PIM1, PIM2, and PIM3 12 .…”

Section: Introductionmentioning

confidence: 99%

PIM2 kinase regulates the expression of TIGIT and energy metabolism on NK cell in multiple myeloma patients

Liu

Wang

et al. 2022

Preprint

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Background: PIM2 kinase play a vital role in the generation of plasma cell and bone loss in multiple myeloma(MM), which highly related to the tumor progression and as a potential therapy target in MM. In immune cell,PIM2 kinase involved in the regulation of lymphocyte like T cell and B cell, However, its role in NK cells remains unclear. Methods: Single-cell RNA sequencing data were analysed the expression of PIM2 kinase in NK cells from MM patients and healthy donors.Immune checkpoint expression, cell apoptosis, and NK cell function had been evaluated through flow cytometry.Then, NCBI, UCSC, JASPAR and GEPIA database were used to predict promoter of TIGIT.NK-92 cells with ETS-1 knockdown were established by using sh-RNA. Kinase functional assay (ADP-Glo) were used to confirm PIM2 inhibitor from 160 kinds of natural flavonoids compound.Samples treated with or without drugs were analyzed using mass spectrometry and RNA-seq. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR) were measured by assay kit. Result: The PIM2 kinase was highly expressed in the NK cells from MM patients based on single-cell sequencing analysis and confirmed in clinical sample by PCR and flow cytometry.Inhibition of PIM2 kinase can increase the function of NK cells and down regulation TIGIT expression. Mechanism, we confirmed that ETS-1 which was directly binding to the promoter of TIGIT was up-regulated by PIM2 kinase, which can lead the strengthened transcription of TIGIT on NK cells.Furthermore, two novel natural flavonoids compound named Kaempferol and Quercetin dihydrate as PIM2 kinase inhibitors exhibiting higher efficiency at low dose in MM cells,while influence the expression of TIGIT and energy metabolism on NK-92 cells. For in vitro experiment,PIM2 kinase inhibitors can activate NK cell killing function and decrease TIGIT expression,while promoted the apoptosis of MM cells irrespective of adding BMSCs or not in co-culture systems BMSCs. Conclusion: PIM2 kinase involved in the regulation of NK cell.Inhibiting PIM2 kinase could down-regulate the expression of TIGIT and improve energy metabolism to enhance NK cell anti myeloma cell.

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Topical advances in PIM kinases and their inhibitors: Medicinal chemistry perspectives

Cited by 19 publications

References 110 publications

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

PIM2 kinase regulates the expression of TIGIT and energy metabolism on NK cell in multiple myeloma patients

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