Publications by authors named "R Kulathila"
A novel capillary-based microfluidic strategy to accelerate the process of small-molecule-compound screening by room-temperature X-ray crystallography using protein crystals is reported. The ultra-thin microfluidic devices are composed of a UV-curable polymer, patterned by cleanroom photolithography, and have nine capillary channels per chip. The chip was designed for ease of sample manipulation, sample stability and minimal X-ray background.
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- SMARCA2 (BRM) is a key ATPase and member of the SWI/SNF chromatin-remodeling complex, which plays a crucial role in regulating gene expression alongside its relative, BRG1 (SMARCA4).
- Current research highlights the lack of small molecules that can specifically inhibit the ATPase activity of SWI/SNF, despite the relevance in cancer, particularly in BRG1-deficient cases.
- New allosteric dual inhibitors targeting both BRM and BRG1 have been developed, showing potential to reduce BRM-dependent gene expression and demonstrate anti-cancer effects in a BRG1-mutant lung tumor model, providing insights into SWI/SNF functions in various health contexts.
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg. Having identified an allosteric, induced pocket of IDH1, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate (), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents.
View Article and Find Full Text PDFHigh throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1. Synthesis of the four separate stereoisomers identified the (,)-diastereomer (, ) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1.
View Article and Find Full Text PDFOncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site.
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