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Kyle R. Brimacombe
National Institutes of Health
70Publications
17H-index
1,391Citations
Publications 75
Newest
#1Tobie D. Lee (NIH: National Institutes of Health)H-Index: 4
#2Olivia W. Lee (NIH: National Institutes of Health)H-Index: 4
Last.Matt Hall (NIH: National Institutes of Health)H-Index: 55
view all 13 authors...
The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit both brain penetration and oral bioavailability of many chemotherapy drugs. Although Food and Drug Administration guidelines require that potential interactions of investigational drugs with P-gp be explored, often this information does not enter into the literature. As such, we developed a high- throughput screen (HTS) to identify substrates of P-gp from a series of chemical libraries, testing a total of 10,804 compoun...
Source
#1Hilary A. Kenny (U of C: University of Chicago)H-Index: 19
#2Madhu Lal-Nag (NIH: National Institutes of Health)H-Index: 8
Last.Ernst Lengyel (U of C: University of Chicago)H-Index: 50
view all 14 authors...
The tumor microenvironment (TME) is a key determinant of metastatic efficiency. We performed a quantitative high throughput screen (qHTS) of diverse medicinal-chemistry tractable scaffolds (44,420 compounds) and pharmacologically active small molecules (386 compounds) using a layered organotypic, robust assay representing the ovarian cancer (OvCa) metastatic TME. This 3D model contains primary human mesothelial cells, fibroblasts and extracellular matrix, to which fluorescently-labeled OvCa cell...
Source
#1Tobie D. Lee (NIH: National Institutes of Health)H-Index: 4
#2Olivia W. Lee (NIH: National Institutes of Health)H-Index: 4
Last.Matt Hall (NIH: National Institutes of Health)H-Index: 55
view all 13 authors...
The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit brain penetration of many chemotherapy drugs. Although Food and Drug Administration guidelines require that potential interactions of investigational drugs with P-gp be explored, often this information does not enter into the literature. As such, we developed a high-throughput screen (HTS) to identify substrates of P-gp from a series of chemical libraries, testing a total of 10,804 compounds, most of which have known me...
Source
#1Sara E. Kearney (NIH: National Institutes of Health)H-Index: 1
#2Gergely Zahoránszky-Kőhalmi (NIH: National Institutes of Health)H-Index: 1
Last.Jason M. Rohde (NIH: National Institutes of Health)H-Index: 10
view all 95 authors...
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemi...
5 CitationsSource
#1Nathan P. Coussens (NIH: National Institutes of Health)H-Index: 13
#2G. Sitta Sittampalam (NIH: National Institutes of Health)H-Index: 7
Last.Christopher P. Austin (NIH: National Institutes of Health)H-Index: 37
view all 45 authors...
3 CitationsSource
#1Nathan P. Coussens (NIH: National Institutes of Health)H-Index: 13
#2Stephen C. Kales (NIH: National Institutes of Health)H-Index: 8
Last.Matt Hall (NIH: National Institutes of Health)H-Index: 55
view all 20 authors...
6 CitationsSource
#1Jason M. Rohde (NIH: National Institutes of Health)H-Index: 10
#2Kyle R. Brimacombe (NIH: National Institutes of Health)H-Index: 17
Last.Matthew B. Boxer (NIH: National Institutes of Health)H-Index: 22
view all 15 authors...
Abstract Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhi...
4 CitationsSource
#1Daniel J. Urban (NIH: National Institutes of Health)H-Index: 20
#2Natalia J. Martinez (NIH: National Institutes of Health)H-Index: 5
Last.Matt Hall (NIH: National Institutes of Health)H-Index: 55
view all 25 authors...
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a cancer target, a number of small molecule inhibitors have been developed to specifi...
8 CitationsSource
#1Ganesha Rai (NIH: National Institutes of Health)H-Index: 20
#2Kyle R. Brimacombe (NIH: National Institutes of Health)H-Index: 17
Last.David J. Maloney (NIH: National Institutes of Health)H-Index: 29
view all 29 authors...
We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicrom...
17 CitationsSource
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