A5060078114- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Gastrointestinal Tumor Research and Treatment
- Lung Cancer Treatments and Mutations
- Sarcoma Diagnosis and Treatment
- Lung Cancer Research Studies
- Peptidase Inhibition and Analysis
- Cancer, Hypoxia, and Metabolism
- Colorectal Cancer Treatments and Studies
- Signaling Pathways in Disease
- Cancer therapeutics and mechanisms
- Enzyme function and inhibition
- Neurofibromatosis and Schwannoma Cases
- Protein Degradation and Inhibitors
- Electric Motor Design and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Enzyme Structure and Function
- Geophysical Methods and Applications
- Light effects on plants
- Multiple Myeloma Research and Treatments
- Algal biology and biofuel production
- 14-3-3 protein interactions
- Biochemical and Molecular Research
- ATP Synthase and ATPases Research
Diamond Materials (United States)
2024
Takeda (United States)
2022
Blackstone (United States)
2022
Ariadne Diagnostics (United States)
2012-2016
Stony Brook University
1976
State University of New York
1976
In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within ALK domain have emerged as a major resistance mechanism to both first- and second-generation inhibitors. This report describes design synthesis series 2,4-diarylaminopyrimidine-based potent selective inhibitors culminating in identification investigational clinical candidate brigatinib. A unique structural...
Abstract Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy often limited by acquisition polyclonal secondary resistance mutations in KIT, with those located activation (A) loop (exons 17/18) being particularly problematic. Here, we explore KIT-inhibitory activity ponatinib preclinical models describe initial characterization its patients GIST. Experimental Design: The cellular...
The activity of the secreted phosphodiesterase autotaxin produces inflammatory signaling molecule LPA and has been associated with a number human diseases including idiopathic pulmonary fibrosis (IPF). We screened single DNA-encoded chemical library (DECL) 225 million compounds identified series potent inhibitors. Optimization this led to discovery compound 1 (X-165), highly potent, selective, bioavailable small molecule. Cocrystallization demonstrated that it novel binding mode occupying...
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in glycolysis pathway. Cancer cells rely heavily on instead oxidative phosphorylation to generate ATP, a phenomenon known as Warburg effect. The inhibition LDH-A by small molecules is therefore interest for potential cancer treatments. We describe identification optimization inhibitors fragment-based drug discovery. applied ligand based NMR screening identify low affinity fragments binding LDH-A....
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors signaling (aromatase inhibitors/SERMs/SERDs) used treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method identify novel PROTAC binding features as the linker positioning, and elements determined directly screen. After ∼120 billion molecules with WT 3 gain-of-function (GOF) mutants, without estradiol that enrich competitively, off-DNA synthesized...
Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles regulation cell proliferation, oncogenic transformation, human carcinogenesis. Since several inhibitors ChoKα display antiproliferative activity both cellular animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate explore ChoKα. Starting from weakly binding fragments,...
Identification of cryptic pockets has the potential to open new therapeutic opportunities by discovering ligand binding sites that remain hidden in static apo structures a target protein. Moreover, allosteric can become valuable for designing target-selective ligands when natural are conserved variants For example, before an pocket was discovered, KRAS considered undruggable due its smooth surface and conservation GDP/GTP across wild type oncogenic isoforms. Recent identification Switch-II
Abstract In non-small cell lung cancer (NSCLC), multiple classes of activating mutations have been identified in EGFR and HER2 that vary widely their sensitivity to available tyrosine kinase inhibitors (TKIs). Erlotinib, gefitinib, afatinib are approved for use patients with the most common forms (ie, exon 19 deletions or L858R substitutions). However, no TKIs activated by any other mutation, including 20 insertions uncommon substitutions, class mutation (including insertions). As inhibition...
In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in epidermal growth factor receptor (EGFR) gene have few effective therapies because this subset mutants is generally resistant to most currently approved EGFR inhibitors. This report describes structure-guided design a novel series potent, irreversible inhibitors mutations, including V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led...
WaterMap and MM-GB/SA scoring methods were applied to an extensive congeneric series of small-molecule SRC inhibitors with high-quality enzyme data well characterized binding modes compare the performance these in this set provide insight into relative strengths each method. Only minor conformational changes bound representative DFG-in class demonstrated previous studies; thus, protein flexibility that normally presents a challenge pose potency predictions was minimized model system. While...
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation toxic oxalate that results from reduced activity alanine–glyoxylate aminotransferase (AGXT) in primary hyperoxaluria (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series potent HAO1 inhibitors, represented by compounds 3–6. Compound 5 was further optimized via various structure–activity relationship (SAR) exploration methods 29, compound with improved potency and...
Identification of cryptic pockets has the potential to open new therapeutic opportunities by discovering ligand binding sites that remain hidden in static apo structures a target protein. Moreover, allosteric can become valuable for designing target-selective ligands when natural are conserved variants For example, before an pocket was discovered, KRAS considered undruggable due its smooth surface and conservation GDP/GTP across wild type oncogenic isoforms. Recent identification Switch-II...
Abstract Amplification of HER2 can drive the proliferation cancer cells, and several inhibitors have been successfully developed. Recent advances in next-generation sequencing now reveal that is subject to mutation, with over 2,000 unique variants observed human cancers. Several examples oncogenic mutations described, these primarily occur at allosteric sites outside ATP-binding site. To identify full spectrum driver aside from a few well-studied mutations, we developed...
Abstract Phosphorus, despite its abundance in the human body, is rarely found drug molecules, with clinical utility limited to a few phosphonic or bisphosponic acid-based medicines and several phosphonate phosphate-containing prodrugs. Concerns about poor cell penetration, low oral bioavailability, biological instability have application of these functional classes design. In our efforts discover pharmaceuticals novel functionality, we introduced neutral, stable phosphine oxide moiety as...
Supplemental Materials from Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms Altered Pharmacologic Effects
Supplemental Materials from Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms Altered Pharmacologic Effects
Supplemental Materials from Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms Altered Pharmacologic Effects
Supplemental Materials from Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms Altered Pharmacologic Effects
<div>Abstract<p>Amplification of HER2 can drive the proliferation cancer cells, and several inhibitors have been successfully developed. Recent advances in next-generation sequencing now reveal that <i>HER2</i> is subject to mutation, with over 2,000 unique variants observed human cancers. Several examples oncogenic mutations described, these primarily occur at allosteric sites outside ATP-binding site. To identify full spectrum driver aside from a few well-studied...
Abstract NSCLC can be divided into a series of genomically-defined subsets, each generally containing distinct molecular driver. The development drugs that specifically target drivers such as mutant EGFR (erlotinib) and ALK fusions (crizotinib) has proven to an effective therapeutic strategy. Despite these treatment advances, drug resistance inevitably occurs via variety mechanisms. Drug resistant point mutations the driver oncogene are common occurrence, with gatekeeper mutants often being...
Abstract Activating mutations in RAS proteins occur ~1/3 of human cancers. These impair the ability protein to hydrolyze GTP GDP. As a result, mutant exist predominantly GTP-bound state, which directly activates aberrant downstream signaling via interaction with effectors such as RAF. Most at glycine 12 KRAS isoform. One mutation, G12C, is particularly common non-small cell lung cancer where it found ~15% adenocarcinomas. Recent efforts have targeted G12C GDP-bound state; however, direct...
Abstract RAS proteins are small GTPases involved in cell proliferation, survival, and differentiation, mutationally activated about a third of all human cancers. These mutations drive cancer by impairing GTPase activity so that the protein is found predominantly its GTP-bound “on” conformation. Most KRAS isoform located at codon 12, glycine P-loop active site. which mutated to cysteine (G12C) particularly common lung cancer. Despite prevalence as an important oncogene decades research,...