New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Zhang, Yu; Liu, Bin; Wu, Xingyu; Li, Ridong; Ning, Xianling; Liu, Yu; Liu, Zhenming; Zhang, Ge; Li, Runtao; Yin, Yuxin

doi:10.1016/j.bmc.2015.05.041

Cited by 43 publications

(10 citation statements)

References 38 publications

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“…Molecular hybridization is a frequently used method in drug design . Dithiocarbamate has been widely used in the design of novel anticancer drugs; − therefore, Yin’s group incorporated the dithiocarbamate moiety with the classic 2,4-diarylaminopyrimidine scaffold for the design of novel FAK inhibitors. The most potent compound 9 (Figure ) inhibits the enzymatic activity of FAK with an IC 50 value of 0.07 nM and shows promising anticancer cellular activity in several cancer cell lines.…”

Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Sun

2020

J. Med. Chem.

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Focal adhesion kinase (FAK) is a nonreceptor intracellular tyrosine kinase that plays an essential role in cancer cell adhesion, survival, proliferation, and migration through both its enzymatic activities and scaffolding functions. Overexpression of FAK has been found in many human cancer cells from different origins, which promotes tumor progression and influences clinical outcomes in different classes of human tumors. Therefore, FAK has been considered as a promising target for small molecule anticancer drug development. Many FAK inhibitors targeting different domains of FAK with various mechanisms of functions have been reported, including kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors. In addition, FAK-targeting PROTACs, which can induce the degradation of FAK, have also been developed. In this Perspective, we summarized the progress in the development of small molecular FAK inhibitors and proposed the perspectives for the future development of agents targeting FAK.

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Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Sun

2020

J. Med. Chem.

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“…We propose that the many types of potential regulatory mechanisms of M 2 PYK allows a fine tuning of activity to a level that supports the metabolic flux levels needed for cancer survival. Therefore, drug activation of M 2 PYK [49][50][51][52][53][54][55][56][61][62][63][64] or expression of M 1 PYK [48] that lacks sensitivity to regulatory mechanisms may introduce too much PYK activity, an outcome that would prevent some glucose-6-phosphate from entering the pentose phosphate pathway to produce the required NADPH. This scenario would be toxic to the cell.…”

Section: An Explanation For Outcomes In Studies With M2pykmentioning

confidence: 99%

A critical review of the role of M2PYK in the Warburg effect

Harris

Fenton

2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M 2 PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M 2 PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M 2 PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M 2 PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M 2 PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M 2 PYK. Although M 2 PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M 2 PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M 2 PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M 2 PYK in the Warburg effect are needed.

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“…Human cDNA for PKM2 was cloned into pET28a + with a N-terminal His tag and purified from Escherichia coli strain BL21 (Invitrogen) using Ni-Agarose beads (Qiagen) as described previously 25 .…”

Section: Methodsmentioning

confidence: 99%

Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

Ning

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8.82 ± 2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.

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New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Cited by 43 publications

References 38 publications

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

A critical review of the role of M2PYK in the Warburg effect

Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

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