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Chowdhury A.R.,Johns Hopkins Hospital | Chowdhury A.R.,GVK Biosciences Private Ltd | Bakshi R.,Johns Hopkins Hospital | Wang J.,Johns Hopkins Hospital | And 9 more authors.
PLoS Pathogens | Year: 2010

Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a.10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing. ©2010 Roy Chowdhury et al.

Duraiswamy A.J.,Experimental Therapeutics Center | Duraiswamy A.J.,GVK Biosciences Private Ltd | Lee M.A.,Experimental Therapeutics Center | Madan B.,National University of Singapore | And 14 more authors.
Journal of Medicinal Chemistry | Year: 2015

Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and function. The inhibition of PORCN could serve as a therapeutic approach for the treatment of a number of Wnt-dependent cancers. Herein, we describe the identification of a Wnt secretion inhibitor from cellular high throughput screening. Classical SAR based cellular optimization provided us with a PORCN inhibitor with nanomolar activity and excellent bioavailability that demonstrated efficacy in a Wnt-driven murine tumor model. Finally, we also discovered that enantiomeric PORCN inhibitors show very different activity in our reporter assay, suggesting that such compounds may be useful for mode of action studies on the PORCN O-acyltransferase. © 2015 American Chemical Society.

Sorra K.,GVK Biosciences Private Ltd | Sorra K.,Jawaharlal Nehru Technological University Anantapur | Mukkanti K.,Jawaharlal Nehru Technological University Anantapur | Pusuluri S.,GVK Biosciences Private Ltd
Tetrahedron | Year: 2012

A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladium-catalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine alkaloids such as circumdatin H, J and other analogues. © 2011 Elsevier Ltd. All rights reserved.

Saha S.,GVK Biosciences Private Ltd | Saha S.,University of Hyderabad | Reddy C.V.R.,University of Hyderabad | Xu S.,University of Southern California | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The synthesis of several analogues of ma'edamines A and B are reported. The synthesized compounds were tested on hormone receptor positive and HER2 positive breast cancer cell lines, by MTT assay. MED-114, 115, 117, 119, 120, 124, 128 and 131 were found to be equally active as Lapatinib on HER2 +ve cell line SKBR3. © 2013 Elsevier Ltd. All rights reserved.

Yanamandra M.,GVK Biosciences Private Ltd | Yanamandra M.,Jawaharlal Nehru University | Mitra S.,GVK Biosciences Private Ltd | Giri A.,Jawaharlal Nehru University
Expert Opinion on Drug Discovery | Year: 2015

Introduction: Phosphoinositide 3-kinases (PI3Ks) constitute one of the most important signaling pathways, playing a vital role in cellular differentiation and proliferation with a key function in cellular receptor triggered signal transduction downstream of tyrosine kinase receptors and/or G-protein coupled receptors. PI3K promotes cell survival proliferation, protein synthesis and glucose metabolism by generating secondary messengers phospholipid phosphatidyl 3,4,5-triphosphate and signaling via AKT/mTOR regulation. Deregulation of PI3K pathways have been observed in cancer, diabetes, neurological and inflammatory diseases and is an attractive target for pharmaceutical industries. Areas covered: In this review, the authors explain different PI3K assay methodologies. Furthermore, the authors summarize the techno-scientific principles and their utility in profiling novel chemical entities against PI3Ks. Specifically, the authors compare different PI3K assay formats explaining their mode of detection as well as their advantages and limitations for drug discovery efforts. Expert opinion: Developing lipid (PI3K) kinase assays involves significant effort and a rational understanding is needed due to the intrinsic lipidic nature of phospholipid phosphatidyl 4,5-biphosphate, which is used as an in vitro substrate for assays with PI3K isoforms. The assay of choice should be versatile, homogenous and definitely adaptable for high-throughput screening campaigns. Additionally, these assays are expected to dissect the mechanism of action of novel compounds (inhibitor characterization) against PI3K. Existing methods provide the versatility to medicinal chemists such that they can choose one or more assay platform to progress their compounds while profiling and/or inhibitor characterization. © 2014 Informa UK, Ltd.

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