Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents

Rathod, Bhagyashri; Chak, Shivam; Patel, Sagarkumar; Shard, Amit

doi:10.1039/d1md00045d

Cited by 21 publications

(10 citation statements)

References 145 publications

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“…Then, the tetrameric forms were changed into monomeric forms of the protein to later use the OPLS3 2015 force field for protein–energy minimisation in protein preparation. Then, crystallised water molecules were removed and the ligand was retained as such [ 41 ]. After protein preparation, a grid was generated around the ligand using receptor grid generation of the glide molecule and applying all the standard glide tool parameters.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K

et al. 2022

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A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a–r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 μM) and 15r (IC50 = 0.85 μM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 μM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G0/G1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 μM and 1 μM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, β-catenin, TAB-182, β-actin, AXIN-2, and NF-κB markers that are involved in the β-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.

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Section: Methodsmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K

et al. 2022

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“…Its precise mechanism is unclear but can involve pleiotropic interactions with signalling factors such as NF-κB, PI3K/Akt/MAPKs, Akt/mTOR, TGF-β, GSK3β, TLR4/Akt signalling pathways, NLRP3 inflammasome, reactive oxygen stress, Bax/Bcl-2, etc. 49 In addition to Shikonin, a number of more recent PKM2 inhibitors have been described (reviewed by Rathod et al 50 ). These include direct inhibitors such as compound 1, an irreversible inhibitor which has antiproliferative activity against several in vitro cancer cell lines at concentrations of 1-2 μM and impairs the growth of tumours in nude mice without acute toxicity.…”

Section: Directly Inhibiting Pkm2mentioning

confidence: 99%

The essential molecular requirements for the transformation of normal cells into established cancer cells, with implications for a novel anti‐cancer agent

Warenius¹

2023

Cancer Reports

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BackgroundNormal adult mammalian cells can respond to oncogenic somatic mutations by committing suicide through a well‐described, energy dependent process termed apoptosis. Cancer cells avoid oncogene promoted apoptosis. Oncogenic somatic mutations are widely acknowledged to be the cause of the relentless unconstrained cell proliferation which characterises cancer. But how does the normal cell with the very first oncogenic mutation survive to proliferate without undergoing apoptosis?New findingsThe phenomena of malignant transformation by somatic mutation, apoptosis, aneuploidy, aerobic glycolysis and Cdk4 upregulation in carcinogenesis have each been extensively discussed separately in the literature but an overview explaining how they may be linked at the initiation of the cancer process has not previously proposed.ConclusionA hypothesis is presented to explain how in addition to the initial oncogenic mutation, the expression of certain key normal genes is, counter‐intuitively, also required for successful malignant transformation from a normal cell to a cancer cell. The hypothesis provides an explanation for how the cyclic amphiphilic peptide HILR‐056, derived from peptides with homology to a hexapeptide in the C‐terminal region of Cdk4, kill cancer cells but not normal cell by necrosis rather than apoptosis.

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“…Due to the central regulatory role of PKM2 in many cancers, there is an urgent need for more effective PKM2 inhibitors. Besides the therapeutic benefit of PKM2 inhibition, it is better to understand the function of PKM2 in normal and cancer cells [72][73][74]. Environmental Health Research Lab (EHRL), Faculty of Sciences V, Lebanese University, Nabatieh, Lebanon; milad.baroud@etud.univ-angers.fr A cytidine analogue and hypomethylating agent, 5-Azacitidine is one of the main drugs being used for the treatment of myelodysplastic syndromes [75].…”

Section: Novel Conjugation Approach To Attain Immunoconjugates Of Monoclonal Antibodies (P02)mentioning

confidence: 99%

29th Annual GP2A Medicinal Chemistry Conference

et al. 2021

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The 29th Annual GP2A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry.

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Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents

Abstract: The review focuses on the tumor pyruvate kinase M2 (PKM2) modulators. Both activators and inhibitors developed against PKM2 are discussed.

Cited by 21 publications

References 145 publications

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K

The essential molecular requirements for the transformation of normal cells into established cancer cells, with implications for a novel anti‐cancer agent

29th Annual GP2A Medicinal Chemistry Conference

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