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Author Aravind Basavapathruni

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Characterization of the Enzymatic Activity of SETDB1 and Its 1:1 Complex with ATF7IP.

Aravind Basavapathruni, Jodi Gureasko, Margaret Porter Scott, William Hermans, Adarsh Godbole, Peter A Leland, P Ann Boriack-Sjodin, Tim J Wigle, Robert A Copeland, Thomas V Riera,

The protein methyltransferase (PMT) SETDB1 is a strong candidate oncogene in melanoma and lung carcinomas. SETDB1 methylates lysine 9 of histone 3 (H3K9), utilizing S-adenosylmethionine (SAM) as the methyl donor and its catalytic activity, has been reported to be regulated by a partner protein ATF7IP. Here, we examine the contribution ... Read more >>

Biochemistry (Biochemistry)
[2016, 55(11):1645-1651]

Cited: 6 times

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Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target.

Nigel J Waters, Scott R Daigle, Bruce N Rehlaender, Aravind Basavapathruni, Carly T Campbell, Tyler B Jensen, Brett F Truitt, Edward J Olhava, Roy M Pollock, Kim A Stickland, Angelos Dovletoglou,

Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is ... Read more >>

J Control Release (Journal of controlled release : official journal of the Controlled Release Society)
[2015, 220(Pt B):758-765]

Cited: 8 times

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Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor.

Aravind Basavapathruni, Edward J Olhava, Scott R Daigle, Carly A Therkelsen, Lei Jin, P Ann Boriack-Sjodin, Christina J Allain, Christine R Klaus, Alejandra Raimondi, Margaret Porter Scott, Angelos Dovletoglou, Victoria M Richon, Roy M Pollock, Robert A Copeland, Mikel P Moyer, Richard Chesworth, Paul G Pearson, Nigel J Waters,

(2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol (EPZ-5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. ... Read more >>

Biopharm Drug Dispos (Biopharmaceutics & drug disposition)
[2014, 35(4):237-252]

Cited: 34 times

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Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

Scott R Daigle, Edward J Olhava, Carly A Therkelsen, Aravind Basavapathruni, Lei Jin, P Ann Boriack-Sjodin, Christina J Allain, Christine R Klaus, Alejandra Raimondi, Margaret Porter Scott, Nigel J Waters, Richard Chesworth, Mikel P Moyer, Robert A Copeland, Victoria M Richon, Roy M Pollock,

Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required ... Read more >>

Blood (Blood)
[2013, 122(6):1017-1025]

Cited: 286 times

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Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

Dongyuan Piao, Aravind Basavapathruni, Pinar Iyidogan, Guangxiu Dai, Wolfgang Hinz, Adrian S Ray, Eisuke Murakami, Joy Y Feng, Fei You, Ginger E Dutschman, David J Austin, Kathlyn A Parker, Karen S Anderson,

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2013, 23(5):1511-1518]

Cited: 3 times

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Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L.

Aravind Basavapathruni, Lei Jin, Scott R Daigle, Christina R A Majer, Carly A Therkelsen, Tim J Wigle, Kevin W Kuntz, Richard Chesworth, Roy M Pollock, Margaret P Scott, Mikel P Moyer, Victoria M Richon, Robert A Copeland, Edward J Olhava,

DOT1L is the human protein methyltransferase responsible for catalyzing the methylation of histone H3 on lysine 79 (H3K79). The ectopic activity of DOT1L, associated with the chromosomal translocation that is a universal hallmark of MLL-rearranged leukemia, is a required driver of leukemogenesis in this malignancy. Here, we present studies on ... Read more >>

Chem Biol Drug Des (Chemical biology & drug design)
[2012, 80(6):971-980]

Cited: 61 times

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Impact of enzyme concentration and residence time on apparent activity recovery in jump dilution analysis.

Robert A Copeland, Aravind Basavapathruni, Mikel Moyer, Margaret Porter Scott,

Jump dilution analysis is commonly used to evaluate the reversibility of inhibition and to quantify the residence time of the inhibitor-enzyme complex. During hit and lead characterization, one sometimes observes apparently linear progress curves after jump dilution that display activity recoveries that are intermediate between those expected for fully reversible ... Read more >>

Anal. Biochem. (Analytical biochemistry)
[2011, 416(2):206-210]

Cited: 30 times

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C-2-aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors.

Roger Hunter, Yassir Younis, Clare I Muhanji, Tanith-Lea Curtin, Kevin J Naidoo, Melissa Petersen, Christopher M Bailey, Aravind Basavapathruni, Karen S Anderson,

Several novel thiourea derivatives of the NNRTI HI-236 substituted at the C-2 oxygen of the phenyl ring have been synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-2 cell cultures. The compounds were synthesized in order to fine-tune the activity of HI-236 as well as to ... Read more >>

Bioorg. Med. Chem. (Bioorganic & medicinal chemistry)
[2008, 16(24):10270-10280]

Cited: 2 times

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Reverse transcription of the HIV-1 pandemic.

Aravind Basavapathruni, Karen S Anderson,

The HIV/AIDS pandemic has existed for >25 years. Extensive work globally has provided avenues to combat viral infection, but the disease continues to rage on in the human population and infected approximately 4 million people in 2006 alone. In this review, we provide a brief history of HIV/AIDS, followed by ... Read more >>

FASEB J. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology)
[2007, 21(14):3795-3808]

Cited: 26 times

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Mechanism of action of (-)-(2R,4R)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl) thymine as an anti-HIV agent.

Eisuke Murakami, Haiying Bao, Aravind Basavapathruni, Christopher M Bailey, Jinfa Du, Holly M Micolochick Steuer, Congrong Niu, Tony Whitaker, Karen S Anderson, Michael J Otto, Phillip A Furman,

(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4yl)thymine (DOT) is a thymidine analogue that has potent in vitro activity against wild-type and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV. For nucleoside analogues to inhibit viral replication, they must be metabolized to the active triphosphate, which inhibits the viral reverse transcriptase (RT). Using purified enzymes, the kinetics of DOT ... Read more >>

Antivir. Chem. Chemother. (Antiviral chemistry & chemotherapy)
[2007, 18(2):83-92]

Cited: 3 times

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[d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor.

Roger Hunter, Clare I Muhanji, Ian Hale, Christopher M Bailey, Aravind Basavapathruni, Karen S Anderson,

The synthesis of bifunctional compound 10 consisting of d4U joined at C-5 to a butynyl spacer attached to HI-236 is reported using a Sonogashira coupling as a key step. As a non-cleavable bifunctional HIV inhibitor incorporating an NRTI with an NNRTI, 10 shows good inhibitory activity (EC(50)=250 nM) against HIV ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & Medicinal Chemistry Letters)
[2007, 17(9):2614-2617]

Cited: 4 times

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Modulation of human immunodeficiency virus type 1 synergistic inhibition by reverse transcriptase mutations.

Aravind Basavapathruni, Johan Vingerhoets, Marie-Pierre de B├ęthune, Raymond Chung, Christopher M Bailey, Jiae Kim, Karen S Anderson,

Synergy between the anti-human immunodeficiency virus type 1 (HIV) nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs) results from a general mechanism in which NNRTIs inhibit ATP-mediated removal of NRTIs from chain-terminated primers by decreasing the maximum rate of removal, thus sustaining NRTI chain termination. With this ... Read more >>

Biochemistry (Biochemistry)
[2006, 45(23):7334-7340]

Cited: 18 times

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Developing novel nonnucleoside HIV-1 reverse transcriptase inhibitors: beyond the butterfly.

Aravind Basavapathruni, Karen S Anderson,

To date three nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus type 1 infection. A limiting factor in the effectiveness of these agents is the development of resistance, manifested by amino acid substitutions within the virally ... Read more >>

Curr. Pharm. Des. (Current pharmaceutical design)
[2006, 12(15):1857-1865]

Cited: 9 times

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Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase.

William L Jorgensen, Juliana Ruiz-Caro, Julian Tirado-Rives, Aravind Basavapathruni, Karen S Anderson, Andrew D Hamilton,

Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & Medicinal Chemistry Letters)
[2006, 16(3):663-667]

Cited: 53 times

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Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Juliana Ruiz-Caro, Aravind Basavapathruni, Joseph T Kim, Christopher M Bailey, Ligong Wang, Karen S Anderson, Andrew D Hamilton, William L Jorgensen,

Following computational analyses, potential non-nucleoside inhibitors of HIV-1 reverse transcriptase have been pursued through synthesis and assaying for anti-viral activity. The general class Het-NH-Ph-U has been considered, where Het is an aromatic heterocycle and U is an unsaturated, hydrophobic group. Results for compounds with Het=2-thiazoyl and 2-pyrimidinyl are the focus ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & Medicinal Chemistry Letters)
[2006, 16(3):668-671]

Cited: 22 times

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Mechanism of action of a novel viral mutagenic covert nucleotide: molecular interactions with HIV-1 reverse transcriptase and host cell DNA polymerases.

Eisuke Murakami, Aravind Basavapathruni, William D Bradley, Karen S Anderson,

A novel non-chain terminating nucleoside analog anti-HIV inhibitor, KP-1212 has been designed to form base pairs with multiple bases that may lead to mutagenesis in the HIV-1 viral genome. After multiple replication cycles, the accumulation of mutations surpasses a crucial threshold beyond which the virus can no longer replicate. HIV-1 ... Read more >>

Antiviral Res. (Antiviral research)
[2005, 67(1):10-17]

Cited: 18 times

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Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs.

Aravind Basavapathruni, Christopher M Bailey, Karen S Anderson,

Combination therapies treating human immunodeficiency virus type 1 (HIV-1) infection delay the emergence of drug-resistant virus and exhibit synergistic inhibition. This synergy is observed within the two classes of inhibitors that target the essential viral reverse transcriptase (RT): the chain-terminating nucleoside analogs (NRTIs) and the allosteric nonnucleosides (NNRTIs) that bind ... Read more >>

J. Biol. Chem. (The Journal of biological chemistry)
[2004, 279(8):6221-6224]

Cited: 32 times

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Probing the molecular mechanisms of AZT drug resistance mediated by HIV-1 reverse transcriptase using a transient kinetic analysis.

Adrian S Ray, Eisuke Murakami, Aravind Basavapathruni, Joseph A Vaccaro, Dagny Ulrich, Chung K Chu, Raymond F Schinazi, Karen S Anderson,

Several hypotheses have been proposed to explain the development of resistance to the anti-HIV drug AZT. Clinical findings show that AZT resistance mutations in HIV-1 reverse transcriptase (RT) not only reduce susceptibility to thymidine analogues but may also confer multi-dideoxynucleoside resistance. In this report, we describe transient kinetic studies establishing ... Read more >>

Biochemistry (Biochemistry)
[2003, 42(29):8831-8841]

Cited: 44 times

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Probing the mechanistic consequences of 5-fluorine substitution on cytidine nucleotide analogue incorporation by HIV-1 reverse transcriptase.

Adrian S Ray, Raymond F Schinazi, Eisuke Murakami, Aravind Basavapathruni, Junxing Shi, Suzana M Zorca, Chung K Chu, Karen S Anderson,

Beta-D and beta-L-enantiomers of 2',3'-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2'-fluorine substitution on the pre-steady state incorporation of 2'-deoxycytidine-5'-monophosphate ... Read more >>

Antivir. Chem. Chemother. (Antiviral chemistry & chemotherapy)
[2003, 14(3):115-125]

Cited: 12 times

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Mechanistic studies to understand the progressive development of resistance in human immunodeficiency virus type 1 reverse transcriptase to abacavir.

Adrian S Ray, Aravind Basavapathruni, Karen S Anderson,

Abacavir has been shown to select for multiple resistant mutations in the human immunodeficiency type 1 (HIV-1) pol gene. In an attempt to understand the molecular mechanism of resistance in response to abacavir, and nucleoside analogs in general, a set of reverse transcriptase mutants were studied to evaluate their kinetics ... Read more >>

J. Biol. Chem. (The Journal of biological chemistry)
[2002, 277(43):40479-40490]

Cited: 39 times

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