Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

Kadam, Kishorkumar S.; Jadhav, Ravindra D.; Kandre, Shivaji; Guha, Tandra; Reddy, M. Mahesh Kumar; Brahma, Manoja K.; Deshmukh, Nitin; Dixit, Amol; Doshi, Lalit; Srinivasan, Shaila; Devle, Jayendra; Damre, Anagha; Nemmani, Kumar V.S.; Gupte, Akshaya; Sharma, Rajiv

doi:10.1016/j.ejmech.2013.05.006

Cited by 13 publications

(8 citation statements)

References 13 publications

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“…Thus targeting ABHD5 will further require understanding of this alternate function and presently limits a dual inhibition approach of both ABHD5 and DGAT1. However several DGAT1 inhibitors are being developed for treating obesity and other metabolic diseases [ 55 , 56 ], and some of these are in clinical trials [ 57 – 59 ]. Utilizing these available small molecule DGAT1 inhibitors in future studies will help assess their therapeutic feasibility in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

Mitra

Gorjala

et al. 2017

BMC Cancer

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BackgroundNeoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth. Previously, we observed that prostate cancer cells uptake and store lipids in the form of lipid droplets, providing building blocks for membrane synthesis, to facilitate proliferation and growth. Mechanisms of lipid uptake, lipid droplet dynamics and their contribution to cancer growth have yet to be defined. This work is focused on elucidating the prostate cancer-specific modifications in lipid storage pathways so that these modified gene products can be identified and therapeutically targeted.MethodsTo identify genes that promote lipid droplet formation and storage, the expression profiles of candidate genes were assessed and compared between peripheral blood mononuclear cells and prostate cancer cells. Subsequently, differentially expressed genes were inhibited and growth assays performed to elucidate their role in the growth of the cancer cells. Cell cycle, apoptosis and autophagy assays were performed to ascertain the mechanism of growth inhibition.ResultsOur results indicate that DGAT1, ABHD5, ACAT1 and ATGL are overexpressed in prostate cancer cells compared to PBMCs and of these overexpressed genes, DGAT1 and ABHD5 aid in the growth of the prostate cancer cells. Blocking the expression of both DGAT1 and ABHD5 results in inhibition of growth, cell cycle block and cell death. DGAT1 siRNA treatment inhibits lipid droplet formation and leads to autophagy where as ABHD5 siRNA treatment promotes accumulation of lipid droplets and leads to apoptosis. Both the siRNA treatments reduce AMPK phosphorylation, a key regulator of lipid metabolism. While DGAT1 siRNA reduces phosphorylation of ACC, the rate limiting enzyme in de novo fat synthesis and triggers phosphorylation of raptor and ULK-1 inducing autophagy and cell death, ABHD5 siRNA decreases P70S6 phosphorylation, leading to PARP cleavage, apoptosis and cell death. Interestingly, DGAT-1 is involved in the synthesis of triacylglycerol where as ABHD5 is a hydrolase and participates in the fatty acid oxidation process, yet inhibition of both enzymes similarly promotes prostate cancer cell death.ConclusionInhibition of either DGAT1 or ABHD5 leads to prostate cancer cell death. Both DGAT1 and ABHD5 can be selectively targeted to block prostate cancer cell growth.

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Section: Discussionmentioning

confidence: 99%

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

Mitra

Gorjala

et al. 2017

BMC Cancer

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“…Compound 2 (DGAT1 inhibition = 84% [1 μM]) that has been developed in‐house was used as a standard during the assay. Compounds possessing the 5‐piperazinethiazole 2,2‐dimethylbutanoic acid scaffold (Table , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ) exhibited moderate DGAT1 inhibition ranging from 22–49%.…”

Section: Resultsmentioning

confidence: 99%

“…A recent publication highlights a series of carboxylic acid derivatives, exemplified by compound 1 , as DGAT1 inhibitors. Of late, we have reported a substituted 5‐phenyl thiazole scaffold, exemplified by compound 2 , for its DGAT1 inhibition. We further identified that combining a carboxylic acid such as 2,2‐dimethylbutanoic acid along with 5‐phenylthiazole, as shown in compound 3 , also exhibited promising DGAT1 inhibition and resulted in a 5‐phenylthiazole 2,2‐dimethylbutanoic acid scaffold .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and DGAT1 Inhibition of New 5‐Piperazinethiazole and 5‐Piperidinethiazole Analogs

Kadam

Gandhi

Reddy

et al. 2014

Journal of Heterocyclic Chem

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In this study, a novel series of 5‐piperazinethiazole 2,2‐dimethylbutanoic acid and 5‐piperidinethiazole 2,2‐dimethylbutanoic acid derivatives have been synthesized. Structures of the newly synthesized compounds have been elucidated using 1H‐NMR, 13C‐NMR, high‐resolution mass spectroscopy, and high‐performance liquid chromatographic analysis. The synthesized derivatives have been evaluated in vitro for their ability to inhibit the enzyme diacylglycerol acyltransferase 1 responsible for triglyceride biosynthesis.

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“…From further optimization of this series, among the analogues the compound shown in Figure 19 appeared as the best candidate for advancement to PK and in vivo efficacy studies based on its superior potency, good selectivity, and other pharmaceutical profiling data in a diet-induced obesity rat model. [109] Based on a literature survey, few DGAT-2 inhibitors have been reported to date. The compound shown in Figure 20 showed good PK properties and significant efficacy in obesity models, with beneficial effects on glucose homeostasis.…”

Section: Dgat Inhibitors Of Synthetic Originmentioning

confidence: 99%

“…The compound shown in Figure 26 displayed excellent DGAT-1 potency (IC 50 = 23 nm) and promising oral PK parameters accompanied by an 87 % decrease in plasma TG levels. [109] Based on a literature survey, few DGAT-2 inhibitors have been reported to date. Jenson Qi [82] has reported some in vitro selectivity profiles of two DGAT-2 inhibitors.…”

Section: Dgat Inhibitors Of Synthetic Originmentioning

confidence: 99%

Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

et al. 2014

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Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors.

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Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

Cited by 13 publications

References 13 publications

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

Synthesis, Characterization, and DGAT1 Inhibition of New 5‐Piperazinethiazole and 5‐Piperidinethiazole Analogs

Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

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