A5100621624- Nitric Oxide and Endothelin Effects
- Enzyme Structure and Function
- Cancer, Hypoxia, and Metabolism
- Metabolism, Diabetes, and Cancer
- Protein Kinase Regulation and GTPase Signaling
- Erythrocyte Function and Pathophysiology
- Protein Structure and Dynamics
- Neonatal Health and Biochemistry
- Legume Nitrogen Fixing Symbiosis
- Mechanisms of cancer metastasis
- Cardiomyopathy and Myosin Studies
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Hemoglobinopathies and Related Disorders
- Plant-Microbe Interactions and Immunity
- Monoclonal and Polyclonal Antibodies Research
- Diabetes Management and Research
- Diet, Metabolism, and Disease
- Metabolomics and Mass Spectrometry Studies
- Artificial Intelligence in Healthcare and Education
- Biomedical Ethics and Regulation
- 14-3-3 protein interactions
- Ion channel regulation and function
- Hearing, Cochlea, Tinnitus, Genetics
- Glycosylation and Glycoproteins Research
Leidos (United States)
2021-2025
Frederick National Laboratory for Cancer Research
2021-2025
Leidos Biomedical Research Inc. (United States)
2024
Indo Soviet Friendship College of Pharmacy
2021-2023
Guru Teg Bahadur Hospital
2020
Christie's
2020
RIKEN Center for Integrative Medical Sciences
2019
Revolution Medicines (United States)
2019
Beth Israel Deaconess Medical Center
2009-2017
Harvard University
2009-2017
Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack specific activators. Here, from a cell-based high-throughput chemical genetic screening, we identified small molecule SC79 that inhibits membrane translocation, but paradoxically activates cytosol. specifically binds PH domain Akt. SC79-bound adopts conformation favorable for phosphorylation by upstream protein...
Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. activity is closely coupled to protein dynamics regulated through two interconverting conformations: state 1 (inactive, effector binding deficient), 2 (active, enabled). Here we use 31P NMR delineate the populations present wild-type (WT) common (G12C, G12D, G12V, G13D, Q61L) bound its natural substrate GTP or a commonly used nonhydrolyzable analogue...
Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K(+)] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations ABCB6 that cosegregated with disease phenotype. The two genomic...
Abstract The glycine to cysteine mutation on codon 12 of KRAS (KRASG12C) is found in ~15% non-small cell lung cancers and a low percentage colorectal pancreatic adenocarcinomas. This activating pushes the balance cellular towards its active, GTP-bound (ON) state that signals downstream drives proliferation. Recently approved inhibitors KRASG12C bind sequester oncogenic protein inactive GDP-bound (OFF) state, have demonstrated clinical efficacy; however, median duration response has been...
Acyl Carrier Protein (ACP) from the malaria parasite, Plasmodium falciparum (PfACP) in its holo form is found to exist two conformational states solution. Unique 3D solution structures of holo-PfACP have been determined for both equilibrium conformations, using high-resolution NMR methods. Twenty each forms on basis 1226 and 1218 unambiguously assigned NOEs (including between 4'-phosphopantetheine prosthetic group (4'-PP) protein), 55 backbone dihedral angles 26 hydrogen bonds. The atomic...
<div>Abstract<p>Approved inhibitors of KRAS<sup>G12C</sup> prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting active, GTP-bound (ON) form. This approach provides no direct target coverage active protein. Expectedly, adaptive resistance to (OFF)-only is observed in association with increased expression activity KRAS<sup>G12C</sup>(ON). To provide optimal coverage, we have developed...
<p>Supplementary Figure S2 shows the electron density map for BBO-8520 bound to KRAS G12C in GDP and GppNHp states</p>
<p>Supplementary Figure S6 shows that BBO-8520 anti-tumor activity in NCI-H358 CDX sotorasib-resistant tumors</p>
<p>Supplementary Figure S1 shows the Kinact/KI values for BBO-8520, sotorasib and adagrasib in biochemical cell-based assays</p>
<p>Supplementary Material and Methods</p>
<p>Supplementary Figure S5 shows that BBO-8520 demonstrates in vivo pERK inhibition, KRAS G12C target engagement and is well tolerated</p>
<p>Supplementary Figure S3 shows the activity of BBO-8520, sotorasib, and adagrasib on Ba/F3 cells with KRAS G12C mutations altered states GTP hydrolysis</p>
<p>Supplementary Figure S4 summarizes cysteine profiling, RNA-seq and kinomescan studies demonstrating that BBO-8520 is selective for KRAS G12C MAPK inhibition.</p>
Approximately 40% of bacterial and mammalian metabolites contain nitrogen-based chemical moieties such as amides, amines, imines. The identification quantification these groups via 2D 1H-15N heteronuclear NMR spectroscopy...
Abstract Sotorasib and adagrasib, allele-specific KRASG12C covalent inhibitors that only target in the inactive GDP-bound (OFF) state, have been approved for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). While these improved treatment paradigm tumors harboring mutations, they are limited their depth duration of response. The suboptimal efficacy (OFF)-only is likely driven by adaptation through increasing population drug-insensitive bound to GTP (ON)....
Abstract KRAS is the most commonly mutated oncogene, altered in approximately 15% of human cancers. While inhibitors KRASG12C have shown promising clinical efficacy, there are currently no approved targeted therapies against other variants, resulting a significant underserved patient population across several major cancer types, including pancreatic carcinoma (PDAC), colorectal (CRC), and non-small cell lung (NSCLC). To address this unmet need, we developed BBO-11818: potent, selective,...
Isolated familial pseudohyperkalemia is a dominant red cell trait characterized by cold-induced 'passive leak' of potassium ions into plasma. The causative gene this condition ABCB6, which encodes an erythrocyte membrane ABC transporter protein bearing the Langereis blood group antigen system. In study analyzing three new families, we report first functional characterization ABCB6 mutants, including homozygous mutation V454A, heterozygous R276W, and compound mutations R276W R723Q (in trans)....