A5008532446- Protein Tyrosine Phosphatases
- ATP Synthase and ATPases Research
- Cytokine Signaling Pathways and Interactions
- Synthesis and biological activity
- PI3K/AKT/mTOR signaling in cancer
- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Marine Toxins and Detection Methods
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- X-ray Diffraction in Crystallography
- Galectins and Cancer Biology
- Crystallization and Solubility Studies
- RNA modifications and cancer
- Computational Drug Discovery Methods
- Cancer Treatment and Pharmacology
- Chemical Synthesis and Reactions
- Phosphodiesterase function and regulation
- Melanoma and MAPK Pathways
- Organic Chemistry Cycloaddition Reactions
- Cancer therapeutics and mechanisms
- Oxidative Organic Chemistry Reactions
- Receptor Mechanisms and Signaling
- Bioactive Compounds and Antitumor Agents
- Neuroscience and Neuropharmacology Research
- Synthesis and pharmacology of benzodiazepine derivatives
Relay Therapeutics (United States)
2023
Massachusetts Institute of Technology
2018-2019
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2016
Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest oncology, both for treating with single agent combination KRAS inhibitor. We were drawn to the pharmacological potential inhibition, especially following initial observation that drug-like compounds could bind an allosteric site enforce closed, inactive state enzyme. Here, we describe identification characterization GDC-1971 (formerly RLY-1971), inhibitor currently...
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated more than 30% human cancers. Specific BRAF MEK inhibitors have shown clinical efficacy patients for treatment BRAF-mutant melanoma. However, majority responses are transient, resistance often associated with reactivation ERK signal pathway. Acquired to these agents has led greater interest ERK, downstream target MAPK De novo design efforts novel scaffold derived from SCH772984 by...
<p>Supplementary Video 1 describes SHP2 domains: the N-SH2 (beige), C-SH2 (light green) and PTP (salmon) domains. Shown in blue is active site of SHP2</p>
<p>Supplementary Video 1 describes SHP2 domains: the N-SH2 (beige), C-SH2 (light green) and PTP (salmon) domains. Shown in blue is active site of SHP2</p>
<p>Allosteric inhibitor SHP099 (1), general pharmacophore (2) and subsequent reported allosteric SHP2 inhibitors (3-6).</p>
<div>Abstract<p>The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in wide range malignancies. Intriguingly, SHP2 also described as critical regulator the tumor microenvironment. Based on this evidence is considered multifaceted target cancer, spurring notion that development direct inhibitors would provide twofold benefit intrinsic and extrinsic inhibition. In review, we will discuss role cancer microenvironment, clinical...
<p>All currently known inhibitors of SHP2 bind at the interface between N-SH2 (beige), C-SH2 (light green) and PTP (salmon) domains, stabilizing inactive conformation SHP2. Shown in blue is inhibitor SHP099, bound to SHP2, which further stabilizes conformation.</p>
<div>Abstract<p>The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in wide range malignancies. Intriguingly, SHP2 also described as critical regulator the tumor microenvironment. Based on this evidence is considered multifaceted target cancer, spurring notion that development direct inhibitors would provide twofold benefit intrinsic and extrinsic inhibition. In review, we will discuss role cancer microenvironment, clinical...
<p>Allosteric inhibitor SHP099 (1), general pharmacophore (2) and subsequent reported allosteric SHP2 inhibitors (3-6).</p>
<p>Supplementary Video 2 shows the conformational changes occurring within SHP2 upon its activation</p>
<p>Supplementary Video 2 shows the conformational changes occurring within SHP2 upon its activation</p>
<p>All currently known inhibitors of SHP2 bind at the interface between N-SH2 (beige), C-SH2 (light green) and PTP (salmon) domains, stabilizing inactive conformation SHP2. Shown in blue is inhibitor SHP099, bound to SHP2, which further stabilizes conformation.</p>
Synthesis of the fused polycyclic ether motif comprising