Ghotas Evindar
GlaxoSmithKline
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Publication
Featured researches published by Ghotas Evindar.
Journal of Medicinal Chemistry | 2013
Jeremy S. Disch; Ghotas Evindar; Cynthia H. Chiu; Charles A. Blum; Han Dai; Lei Jin; Kenneth Lind; Svetlana L. Belyanskaya; Jianghe Deng; Frank T. Coppo; Leah Aquilani; Todd L. Graybill; John W. Cuozzo; Siva Lavu; Cheney Mao; George P. Vlasuk; Robert B. Perni
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.
Journal of Medicinal Chemistry | 2014
Lourdes Encinas; Heather O’Keefe; Margarete Neu; Modesto J. Remuiñán; Amish Patel; Ana Guardia; Christopher P. Davie; Natalia Pérez-Macías; Hongfang Yang; Jeff A. Messer; Esther Pérez-Herrán; Paolo A. Centrella; Daniel Álvarez-Gómez; Matthew A. Clark; Sophie Huss; Gary O’Donovan; Fátima Ortega-Muro; William McDowell; Pablo Castañeda; Christopher C. Arico-Muendel; Stane Pajk; Joaquín Rullas; Iñigo Angulo-Barturen; Emilio Alvarez-Ruiz; Alfonso Mendoza-Losana; Lluís Pagès; Julia Castro-Pichel; Ghotas Evindar
Tuberculosis (TB) is one of the worlds oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.
Bioorganic & Medicinal Chemistry | 2014
Christopher S. Kollmann; Xiaopeng Bai; Ching-Hsuan Tsai; Hongfang Yang; Kenneth Lind; Steven R. Skinner; Zhengrong Zhu; David I. Israel; John W. Cuozzo; Barry Morgan; Koichi Yuki; Can Xie; Timothy A. Springer; Motomu Shimaoka; Ghotas Evindar
The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.
ACS Medicinal Chemistry Letters | 2015
Hongfang Yang; Patricia F Medeiros; Kaushik Raha; Patricia A. Elkins; Kenneth Lind; Ruth Lehr; Nicholas D. Adams; Joelle L. Burgess; Stanley J. Schmidt; Steven David Knight; Kurt R. Auger; Michael D. Schaber; G. Joseph Franklin; Yun Ding; Jennifer L. DeLorey; Paolo A. Centrella; Sibongile Mataruse; Steven R. Skinner; Matthew A. Clark; John W. Cuozzo; Ghotas Evindar
In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.
Bioorganic & Medicinal Chemistry Letters | 2009
Ghotas Evindar; Sylvie G. Bernier; Malcolm J. Kavarana; Elisabeth Doyle; Jeanine Lorusso; Michael Kelley; Keith Halley; Amy Hutchings; Albion D. Wright; Ashis K. Saha; Gerhard Hannig; Barry Morgan; William F. Westlin
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
ACS Medicinal Chemistry Letters | 2013
Hongfeng Deng; Sylvie G. Bernier; Elisabeth Doyle; Jeanine Lorusso; Barry Morgan; William F. Westlin; Ghotas Evindar
To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P1 modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P1 agonist activity with >1000× selectivity over S1P3. The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.
Bioorganic & Medicinal Chemistry Letters | 2009
Ghotas Evindar; Alexander L. Satz; Sylvie G. Bernier; Malcolm J. Kavarana; Elisabeth Doyle; Jeanine Lorusso; Nazbeh Taghizadeh; Keith Halley; Amy Hutchings; Michael Kelley; Albion D. Wright; Ashis K. Saha; Gerhard Hannig; Barry Morgan; William F. Westlin
In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
Bioorganic & Medicinal Chemistry Letters | 2010
Ghotas Evindar; Sylvie G. Bernier; Elisabeth Doyle; Malcolm J. Kavarana; Alexander L. Satz; Jeanine Lorusso; Heather S. Blanchette; Ashis K. Saha; Gerhard Hannig; Barry Morgan; William F. Westlin
In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
Journal of Medicinal Chemistry | 2016
Nestor O. Concha; Jianzhong Huang; Xiaopeng Bai; Andrew Benowitz; Pat Brady; LaShadric C. Grady; Luz Helena Kryn; David J. Holmes; Karen A. Ingraham; Qi Jin; Laura Pothier Kaushansky; Lynn McCloskey; Jeffrey A. Messer; Heather O’Keefe; Amish Patel; Alexander L. Satz; Robert H. Sinnamon; Jessica Schneck; Steve R. Skinner; Jennifer Summerfield; Amy E Taylor; J. David Taylor; Ghotas Evindar; Robert A. Stavenger
Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target.
ACS Chemical Biology | 2017
Zhengrong Zhu; Alex Shaginian; LaShadric C. Grady; Thomas O’Keeffe; Xiangguo E. Shi; Christopher P. Davie; Graham L. Simpson; Jeffrey A. Messer; Ghotas Evindar; Robert N. Bream; Praew Thansandote; Naomi R. Prentice; Andrew M. Mason; Sandeep Pal
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.